Leukotriene B4 antagonist compounds and method for treatment

ABSTRACT

Novel amidinophenol derivatives of formula (IB)  
                 
 
     and processes for the preparation thereof; compositions containing a compound of formula (IB) as active ingredient useful as antagonists of leukotine B 4  and inhibitors of phospholipase A 2  and/or trypsin; methods for preventing or treating diseases induced by phospholipase A 2  and/or trypsin comprising administering to a patient a compound of formula (IB); and methods for treating diseases induced by leukotine B 4  comprising administering to a patient a compound of formula (IB) or a known amidinophenol derivative of formula (IA)

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to amidinophenol derivatives,processes for the preparation thereof and the use thereof as leukotrieneB₄ (LTB₄)antagonists, phospholipase A₂ inhibitors, and trypsininhibitors.

[0003] More particularly, it relates to LTB₄ antagonists containing anamidinophenol derivative of the formula (IA):

[0004] (wherein various symbols are the same meanings as hereafterdescribed), as the active ingredient; to

[0005] amidinophenol derivatives of the formula (IB):

[0006] (wherein various symbols are the same meanings as hereafterdescribed) and processes for the preparation thereof; and to LTB₄antagonists, phospholipaseA₂ inhibitors and trypsin inhibitorscontaining a compound of formula (IB) as the active ingredient.

[0007] 2. Description of Related Art

[0008] The metabolic pathways by which various compounds arebiosynthesized, in vivo, from arachidonic acid as a common startingmaterial are called the arachidonic acid cascade.

[0009] Lipoxygenase, for example, 5-lipoxygenase, 12-lipoxygenase or15-lipoxygenase, respectively, acts on arachidonic acid to produce5-HPETE, 12-HPETE or 15-HPETE from arachidonic acid.

[0010] The above mentioned HPETEs are converted into 5-HETE, 12-HETE or15-HETE, by converting a peroxy group into a hydroxy group by the actionof peroxidase, and 5-HPETE is also converted into LTA₄.

[0011] LTA₄ is converted into LTB₄ or LTC₄ by enzymatic reaction (seeBiochem. Biophys. Res. Commun., 91, 1266 (1979), Prostaglandins, 19(5),645).

[0012] Recently a number of properties of LTB₄ have been revealed.

[0013] It is understood that LTB₄ has strong chemotactic and adhesiveactivity and degranulation activity on leukocytes (see Nature, 286, 264(1980), Proc. Nat. Acad. Sci. USA, 78, 3887 (1981)).

[0014] LTB₄ also has strong calcium ionophore action, and attacksvarious cells, and it is considered to accelerate release of metabolitesof arachidonic acid from these cells (see J. Biol. Chem, 257, 4746(1982)).

[0015] High levels of LTB₄ have also been found at sites of variousinflammations, for example, rheumatism, spondyl arthritis, gout,psoriasis, ulcerative colitis and respiratory tract diseases, therebydemonstrating that LTB₄ is closely associated with various inflammations(see J. Clin. Invest., 66, 1166 (1980); Lancet 11 1122-1123 (1982); J.Invest. Dermatol., 82, 477-479 (1984); Gastroenterology 86, 453-460(1984)).

[0016] It is therefore considered that LTB₄ antagonists are useful asanti-inflammatory agents or anti-allergic agents.

[0017] It is known that LTB₄ antagonists are also useful for thetreatment of rheumatoid arthritis, inflammatory bowel diseases,psoriasis, nonsteroidal anti-inflammatory agent-induced stomachdiseases, adult respiratory distress syndrome, cardiac infarction,allergic rhinitis, hemodialysis-induced neutropenia, anaphase asthma(see the specification of the Japanese Patent Kokai No. 5-239008).

[0018] Phospholipase A₂ (PLA₂) is an enzyme which acts on phospholipidsexisting in cell membranes. It hydrolyzes an ester bond at the secondposition of the phospholipids. There are two known kinds of PLA₂,membrane-associated PLA₂ and pancreatic PLA₂.

[0019] Membrane-associated PLA₂ acts on phospholipids to releasearachidonic acid (AA) from the phospholipids. The AA is converted intoprostaglandins, thromboxanes and leukotrienes, which are physiologicallyactive substances inducing various inflammatory diseases and allergicdiseases.

[0020] On the other hand, pancreatic PLA₂ degrades phospholipids anddestroys cell membranes, thereby producing lysolecithin having strongcytotoxicity. Recently, much importance has been attached topancreatitis, severity in pancreatitis and multiple organ failureinduced by this destructive activity on cell membranes.

[0021] It is also reported that membrane-associated PLA₂ is alsoconcerned with these diseases.

[0022] Accordingly, the inhibition of PLA₂ leads to the suppression ofthe release of AA, a precursor of various physiologically activesubstances, and therefore, it is considered to be useful for theprevention and/or the treatment of various inflammatory and allergicdiseases. Furthermore, it is considered to be useful for the preventionand/or the treatment of pancreatitis, severity in pancreatitis andmultiple organ failure due to the inhibition of the destructive activityon cell membranes.

[0023] It is also known that the inhibition of various proteases such astrypsin, plasmin, thrombin, kallilrein, especially trypsin is useful forthe prevention and/or the treatment of disseminated intravascularcoagulation, pancreatitis, severity in pancreatitis and multiple organfailure.

[0024] In the specifications of EP-A-588655 and 656349, it is disclosedthat cetain amidinophenol compounds of the formula (IA) depictedhereinafter have an inhibitory activity on PLA₂ and an inhibitoryactivity on trypsin and are useful for the prevention and/or thetreatment of various inflammatory or allergic diseases, disseminatedintravascular coagulation, pancreatitis, severity in pancreatitis andmultiple organ failure.

[0025] Several amidinophenol derivatives are known to be LTB₄antagonists. They are disclosed in WO 94/11341, the specification ofJapanese Patent Kokai No. 5-239008 and EP-518819. In these applications,it is disclosed that amidinophenyloxy (thio) alkyloxy (thio) benzamideis useful as an LTB₄ antagonist.

[0026] For example, it is described in the specification of EP-518819that compounds of the formula (A):

[0027] wherein R^(1a) is amino which is mono- or disubstituted by asubstituent selected from an aliphatic hydrocarbon radical, anaraliphatic hydrocarbon radical, an aromatic radical, and acycloaliphatic hydrocarbon radical or is amino which is disubstituted bya divalent aliphatic hydrocarbon radical; R^(2a) is hydrogen, halogen,trifluoromethyl, an aliphatic hydrocarbon radical, or is hydroxy whichis etherified by an aliphatic alcohol, araliphatic alcohol, or aromaticalcohol or which is esterified by an aliphatic or araliphatic carboxylicacid;

[0028] R^(3a) is hydrogen or an acyl radical which is derived from anorganic carbonic acid, an organic carboxylic acid, a sulfonic acid, or acarbamic acid; X_(1a) and X_(3a), independently of one another, areoxygen (—O—) or sulphur (—S—);

[0029] X_(2a) is a divalent aliphatic hydrocarbon radical which may beinterrupted by an aromatic radical;

[0030] wherein the phenyl rings of formula (A) may be, independently ofone another, further substituted by one or more substituents selectedfrom halogen, trifluoromethyl, an aliphatic hydrocarbon radical,hydroxy, and hydroxy which is etherified by an aliphatic alcohol orwhich is esterified by an aliphatic or araliphatic carboxylic acid;

[0031] wherein aryl moieties in the above definitions may be,independently of one another, further substituted by one or moresubstituents selected from halogen, trifluoromethyl, an aliphatichydrocarbon radical, hydroxy, and hydroxy which is etherified by analiphatic alcohol or which is esterified by an aliphatic or araliphaticcarboxylic acid; and

[0032] wherein a cycloaliphatic hydrocarbon radical may be substitutedby an aliphatic radical;

[0033] and pharmaceutically acceptable salts thereof are useful as LTB₄antagonist.

[0034] 3. Comparison with the Related Arts

[0035] In the amidinophenyloxy(thio)alkoxy(thio)benzamide compoundsrepresented by EP-518819 as prior art, it can be seen that—X_(1a)—X_(2a)—X_(3a)— must be —O(or S)-alkylene-O(or S)—, with theproviso that the alkylene may be interrupted by an aromatic group.

[0036] It has now been discovered that compounds in which it isessential that the amidinophenyl group is bonded to the phenyl group viaan ester or amide group possess useful properties as LTB₄ antagonistsand as inhibitors of phospholipase A₂ and/or trypsin.

SUMMARY OF THE INVENTION

[0037] The present invention relates to the discovery that amidinophenolderivatives defined by formulas (IA) and (IB) have a strong antagonisticactivity on LTB₄ and thus are useful for the prevention or treatment ofdiseases induced by LTB₄.

[0038] The present invention also relates to the discovery thatcompounds of formula (IB) have an inhibitory activity on phospholipaseA₂ and an inhibitory activity on trypsin and thus are useful inpreventing or treating conditions associated with the activity of theseenzymes, such as various inflammatory and allergic diseases,disseminated intravascular coagulation, pancreatitis, severity inpancreatitits and multiple organ failure.

[0039] Compunds of formula (IA) and processes for the preparationthereof are known and disclosed in EP-A-588655 and EP-A-656349.Compounds of formula (IB) are novel and described below.

DESCRIPTION OF THE INVENTION

[0040] The present invention relates to

[0041] 1) a new amidinophenol derivative of the formula (IB):

[0042] is a group of the formula:

[0043] wherein R⁰ is hydrogen, C1-4 alkyl, or C1-4 alkoxy,

[0044] T is NH or oxygen,

[0045] E is a single bond, or a group of the formula:

[0046] A₀ is selected from the group consisting of a single bond, C1-4alkylene, -oxy-(C1-4)alkylene-, -thio-(C1-4)alkylene-, C2-8 alkenylene,and C2-8 alkenylene substituted by carboxy or C1-4 alkoxycarbonyl,

[0047] R¹⁰⁰, R²⁰⁰, R³⁰⁰ and R⁴⁰⁰ each independently, is hydrogen or C1-4alkyl, R is a group of the formula:

[0048] is a 4-10 membered hetero ring containing one or two nitrogenatoms, R⁵⁰, R⁶⁰ and R⁷⁰ each independently, is,

[0049] (i) hydrogen,

[0050] (ii) C1-8 alkyl,

[0051] (iii) C2-8 alkenyl

[0052] (iv) —COOR¹¹⁰, wherein R¹¹⁰ is hydrogen, C1-4 alkyl, or C1-4alkyl substituted by phenyl,

[0053] (v) —(C1-8 alkylene)-COOR¹¹⁰, wherein R¹¹⁰ has the same meaningas defined above,

[0054] (vi) —(C2-8 alkenylene)-COOR¹¹⁰, wherein R¹¹⁰ has the samemeaning as defined above,

[0055] (vii) C4-7 cycloalkyl,

[0056] (viii) —(C1-4 alkylene)-(4-7 membered hetero ring containing oneoxygen),

[0057] (ix) —(C1-4 alkylene)-(4-7 membered hetero ring containing onenitrogen),

[0058] (x) phenyl,

[0059] (xi) C1-8 alkyl substituted by one or two phenyl,

[0060] (xii) —(C1-4 alkylene)-O-benzoyl,

[0061] (xiii) -(C1-4 alkylene)-CONH—(C1-4 alkylene)-NR¹²⁰R¹³⁰,

[0062] (xiv) —(C1-4 alkylene)-COO—(C1-4 alkylene)-NR¹²⁰R¹³⁰,

[0063] (xv) —(C1-4 alkylene)-COO-amidinophenyl,

[0064] (xvi) —(C1-4 alkylene)-CONH—(C1-4 alkyl substituted by one or twoCOOR¹¹⁰), wherein R¹¹⁰ has the same meaning as defined above,

[0065] (xvii) —(C1-4 alkylene)-CONR¹²⁰R¹³⁰, or

[0066] (xviii) (C1-4) alkoxy (C1-4) alkyl,

[0067] R⁸⁰ and R⁹⁰ each independently, is C1-4 alkyl or —(C1-4alkylene)-phenyl,

[0068] R¹²⁰ and R¹³⁰ each independently, is hydrogen, C1-4 alkyl, orC2-8 alkenyl, with the provisos that:

[0069] (1) R⁵⁰ and R⁶⁰ in the formulae (i) and (iii), and R⁵⁰, R⁶⁰ andR⁷⁰ in the formulae (ii) and (iv), do not represent hydrogen at the sametime,

[0070] (2) when at least one substituent in R⁵⁰, R⁶⁰, R⁷⁰ and A₀represents a substituent containing —COO-t-Bu, the other groups do notrepresent groups containing carboxy,

[0071] (3) R¹²⁰ and R¹³⁰ do not represent hydrogen at the same time,

[0072] (4) when

[0073] T is oxygen,

[0074] the group:

[0075] is the formula (i) as hereinbefore described,

[0076] E is a single bond,

[0077] A₀ is a single bond, C1-4 alkylene or vinylene which isoptionally substituted by one or two C1-4 alkyl, and

[0078] R is the formula (i) as described above,

[0079] then at least one group in R⁵⁰, R⁶⁰ and R⁷⁰ is

[0080] (viii) —(C1-4 alkylene)-(4-7 membered hetero ring containing oneoxygen),

[0081] (ix) —(C1-4 alkylene)-(4-7 membered hetero ring containing onenitrogen),

[0082] (x) phenyl,

[0083] (xi) C1-8 alkyl which is substituted by one or two phenyl,

[0084] (xii) —(C1-4 alkylene)-O-benzoyl,

[0085] (xiii) —(C1-4 alkylene)-CONH—(C1-4 alkylene)-NR¹²⁰R¹³⁰,

[0086] (xiv) —(C1-4 alkylene)-COO—(C1-4 alkylene)-NR¹²⁰R¹³⁰,

[0087] (xv) —(C1-4 alkylene)-COO-amidinophenyl,

[0088] (xvi) —(C1-4 alkylene)-CONH—(C1-4 alkyl substituted by one or twoCOOR¹¹⁰), wherein R¹¹⁰ has the same meaning as defined above,

[0089] (xvii) —(C1-4 alkylene)-CONR¹²⁰R¹³⁰, or

[0090] (xviii) (C1-4) alkoxy (C1-4) alkyl;

[0091] (5) when

[0092] T is oxygen,

[0093] the group

[0094] is the formula (i) as hereinbefore defined,

[0095] E is a single bond,

[0096] A₀ is a single bond, C1-4 alkylene or vinylene optionallysubstituted by one or two C1-4 alkyl, and

[0097] R is the formula (ii) as defined above,

[0098] then R⁵⁰, R⁶⁰ and R⁷⁰ do not represent hydrogen;

[0099] and non-toxic salts thereof or non-toxic acid addition saltsthereof,

[0100] 2) a method for the prevention and/or treatment of diseasesinduced by leukotriene B₄, which comprises the administration to apatient of an effective amount of a compound of the formula (IA):

[0101] wherein R¹ and R² each independently, is:

[0102] (i) hydrogen, or

[0103] (ii) —COOR⁴ wherein R⁴ is C1-3 alkyl;

[0104] A is

[0105] (i) a single bond,

[0106] (ii) C1-4 alkylene, or

[0107] (iii) —C(R⁵)═C(R⁶)—, wherein R⁵ and R⁶ each independently, ishydrogen or C1-4 alkyl;

[0108] R³ is

[0109] (i) —CON(R⁷)R⁸,

[0110] (ii) —CONR⁹-CH(R⁷)R⁸, or

[0111] (iii)

[0112] wherein R⁷ and R⁸ each independently, is

[0113] (1) hydrogen,

[0114] (2) phenyl,

[0115] (3) —(C1-4 alkylene)-phenyl,

[0116] (4)-(C1-4 alkylene)-phenyl is substituted by one or two—R¹¹—COOR¹², wherein R¹¹ is a single bond or C1-8 alkylene, and

[0117] R¹² is hydrogen or C1-4 alkyl,

[0118] (5) C1-5 alkyl,

[0119] (6) C2-10 alkenyl containing one to three double bonds,

[0120] (7) —R^(11a)—COOR¹²,

[0121] wherein R^(11a) is

[0122] (a) a single bond,

[0123] (b) C1-8 alkylene,

[0124] (c) C2-8 alkenylene, or

[0125] (d) C4-8 alkenylene in which one or two carbon atoms in the mainchain are replaced by sulfur, and R¹² has the same meaning as definedabove, or

[0126] (8) C3-7 cycloalkyl;

[0127] R⁹ is

[0128] (1) hydrogen,

[0129] (2) —R¹ ¹—COOR¹², wherein R¹¹ and R¹² have the same meanings asdefined above, or

[0130] (3) C2-6 alkoxyalkyl;

[0131] the group:

[0132] is a 4-7 membered mono hetero ring contain one or two nitrogen;

[0133] R¹⁰ is

[0134] (1) hydrogen, or

[0135] (2) —(C1-4 alkylene)-phenyl,

[0136] with the proviso that:

[0137] (1) both R⁷ and R⁸ do not represent hydrogen at the same time,

[0138] (2) when at least one group in R⁷, R⁸, and R⁹ represent the groupcontaining —COO-t-Bu, the other groups do not represent the groupscontaining carboxy;

[0139] or non-toxic salts thereof and non-toxic acid-addition saltsthereof,

[0140] 3) processes for the preparation of the compound of the formula(IB),

[0141] 4) LTB₄ antagonists containing a compound of the formula (IB) andnon-toxic salts thereof or non-toxic acid addition salts thereof, as theactive ingredient, and

[0142] 5) phospholipaseA₂ and trypsin inhibitors containing a compoundof the formula (IB) and non-toxic salts thereof or non-toxic acidaddition salts thereof, as the active ingredient.

[0143] The compounds of the invention may form hydrates; it is to beunderstood that such hydrates form part of the present invention andthat references to the compounds in this specification, including theaccompanying claims, are to be understood as embracing the hydrates.

[0144] It will be understood that formulae (i) and (ii) for the symbol Rmay overlap: formula (ii) should be construed as excluding thosegroupings already embraced by formula (i).

[0145] Throughout the specification, it will be understood by thoseskilled in the art that all isomers are included in the presentinvention. For example, the alkyl, alkoxy, alkylene, alkenylene andalkynylene groups include straight-chain and also branched-chain ones,and the double bonds in the alkenylene group include E, Z and EZmixtures. Accordingly, all isomers produced by the existence ofasymmetric carbon atoms are included in the present invention whenbranched-chain alkyl, alkoxy, alkylene, alkenylene and alkynylene arepresent.

[0146] Explanation of various symbols in the formula (IB) is givenbelow.

[0147] The C1-3 alkyl group means methyl, ethyl, propyl and the isomersthereof. C1-4 alkyl group means methyl, ethyl, propyl, butyl, and theisomers thereof. C1-5 alkyl group means methyl, ethyl, propyl, butyl,pentyl and the isomers thereof.

[0148] C1-4 alkylene group means methylene, ethylene, trimethylene,tetramethylene and the isomers thereof. C1-8 alkylene group meansmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, and the isomers thereof.

[0149] C2-6 alkoxyalkyl group means ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene which are interrupted byoxygen except end.

[0150] C4-8 alkenylene group means tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene in which a —CH₂—CH₂—grouping (which is not at either end of the group) is replaced by adouble bond.

[0151] C2-8 alkenylene group containing one to three double bonds meansethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene or octamethylene in which one to three groupings—CH₂—CH₂— (except those at each end of the group) are replaced by doublebonds.

[0152] C3-7 cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

[0153] The 4-7 membered hetero ring containing one or two nitrogenmeans, for example, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolidinyl,pyridinyl, piperidinyl, pyrazinyl, piperazinyl or pyrimidinyl.

[0154] Further explanation of various symbols in the formula (IB) isgiven below.

[0155] In the formula (IB), C1-4 alkyl represented by R⁰, R¹⁰⁰, R²⁰⁰,R³⁰⁰, R⁴⁰⁰, R⁵⁰, R⁶⁰, R⁷⁰, R⁸⁰, R⁹⁰, R¹²⁰ and R¹³⁰, and that in R⁰,R¹⁰⁰, R²⁰⁰, R³⁰⁰, R⁴⁰⁰, R⁵⁰, R⁶⁰, R⁷⁰, R⁸⁰, R⁹⁰, R¹²⁰ and R¹³⁰, meansmethyl, ethyl, propyl, butyl and the isomers thereof.

[0156] In the formula (IB), C1-4 alkyl represented by R⁰ and A₀, andthat in R⁰ and A₀ means methoxy, ethoxy, propoxy, butoxy and the isomersthereof.

[0157] In the formula (IB), C1-4 alkylene represented by A₀, and that inA₀, means methylene, ethylene, trimethylene, tetramethylene and theisomers thereof.

[0158] In the formula (IB), C2-8 alkenylene represented by A₀, and thatin A₀, means ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene and the isomers thereof,having one, two or three double bonds.

[0159] In the formula (IB), C1-8 alkyl represented by R⁵⁰, R⁶⁰ and R⁷⁰,and that in R⁵⁰, R⁶⁰ and R⁷⁰, means methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and the isomers thereof.

[0160] In the formula (IB), C2-8 alkenyl represented by R⁵⁰, R⁶⁰ andR⁷⁰, and that in R⁵⁰, R⁶⁰ and R⁷⁰, mean methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and the isomers thereof, having one, two orthree double bonds.

[0161] In the formula (IB), 4-7 cycloalkyl represented by R⁵⁰, R⁶⁰ andR⁷⁰, and that in R⁵⁰, R⁶⁰ and R⁷⁰, mean cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

[0162] In the formula (IB), examples of the 4-7 membered hetero ringcontaining one oxygen (which may be partially or fully saturated)represented by R⁵⁰, R⁶⁰ and R⁷⁰, and that in R⁵⁰, R⁶⁰ and R⁷⁰, arefuryl, pyranyl, dihydrofuryl, dihydropyranyl, tetrahydrofuryl andtetrahydropyranyl.

[0163] In the formula (IB), examples of the 4-7 membered hetero ringcontaining one nitrogen (which may be partially or fully saturated)represented by R⁵⁰, R⁶⁰ and R⁷⁰, and that in R⁵⁰, R⁶⁰ and R⁷⁰, arepyrrolyl, pyridinyl, piperidinyl, pyrrolinyl, pyrrolidinyl anddihydropyridinyl.

[0164] In the formula (IB), when R is the formula represented by (vi),examples of the 4-10 membered hetero ring containing one or twonitrogen, (which may be partially or fully saturated) are pyrrolyl,pyridinyl, pyrrolinyl, pyrrolidinyl, dihydropyridinyl, imidazolyl,piperidinyl, imidazolinyl, imidazolidinyl, pyrimidinyl, pyridazinyl,pyrazinyl, indolyl and tetrahydroindolyl.

[0165] Preferred Compound

[0166] Preferred formula (IB) compounds of the present invention arethose described in the Examples and the following compounds. TABLE 1

Preferable groups as R

[0167] TABLE 2

Preferable groups as R

[0168] TABLE 3

Preferable groups as R

[0169] TABLE 4

Preferable groups as R

[0170] TABLE 5

Preferabie groups as R

[0171] TABLE 6

Preferabie groups as R

[0172] TABLE 7

Preferable groups as R

[0173] TABLE 8

Preferable groups as R

[0174] TABLE 9

Preferable groups as R

[0175] TABLE 10

Preferable groups as R

[0176] TABLE 11

Preferable groups as R

[0177] TABLE 12

Preferable groups as R

[0178] TABLE 13

Preferable groups as R

[0179] TABLE 14

Preferabel groups as R

[0180] TABLE 15

Preferable groups as R

[0181] TABLE 16

Preferable groups as R

[0182] Pharmaceutical compositions of the present invention can beprepared using one active ingredient or two or more active ingredients.

[0183] Salts and Acid-additon Salts

[0184] Compounds of the formulae (IA) and (IB) of the present inventionmay be converted into the corresponding salts and acid-addition salts byknown methods. Nontoxic and water-soluble salts are preferred.

[0185] Suitable salts include the salts of alkali metals (sodium,potassium etc.), alkaline-earth metal (calcium, magnesium etc.),ammonium salts, salts of pharmacoligically acceptable organic amines(tetramethyl ammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenetylamine, piperidine,monoethanolamine, diethanolamine, tris (hydroxymethyl)aminomethane,lysine, arginine, N-methyl-D-gulcane etc).

[0186] Suitable acid-addition salts include the salts with inorganicacids such as hydrochloric acid, and the salts with organic acids suchas acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalicacid, fumaric acid, maleic acid, citric acid, benzoic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, isethionic acid, glucuronic acid and gluconicacid. Preferred salts include the salts with acids such as hydrochloricacid, methanesulfonic acid, acetic acid and trifluoroacetic acid.

[0187] Preparation of Compounds

[0188] The compounds of the formula (IA) may be prepared by methodsknown per se, as defined in published applications EP-A-588655 andEP-A-656349. The formula (1B) compounds of the present invention may beprepared by forming an ester or amide bond between a compound of theformula (II):

[0189] (wherein the various symbols have the same meanings ashereinbefore defined) with a compound of the formula (III):

[0190] (wherein the various symbols have the same meanings ashereinbefore defined). The esterification reaction and the reaction toform an amide are known and can be carried out by known method, forexample:

[0191] (1) using an acid halide,

[0192] (2) using a mixed acid anhydride or

[0193] (3) using a condensing agent.

[0194] Esterification can be carried out, for example, as follows:

[0195] (1) the method using an acid halide may be carried out, forexample, by reacting a carboxylic acid with an acid halide (e.g., oxalylchloride, thionyl chloride etc.) in an inert organic solvent (e.g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) orwithout a solvent at from −20° C. to the reflux temperature of thesolvent, and then by reacting the acid halide obtained with acorresponding alcohol in the presence of a tertiary amine (e.g.,pyridine, triethylamine, diethylaniline, diethylaminopyridine etc.) inan inert organic solvent (e.g., chloroform, methylene chloride, diethylether, tetrahydrofuran etc.) at a temperature of from 0° C. to 40° C.;

[0196] (2) the method using a mixed acid anhydride may be carried out,for example, by reacting a carboxylic acid and an acid halide (e.g.,pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acidderivative (e.g., ethyl chloroformate, isobutyl chloroformate etc.) inthe presence of a tertiary amine (e.g., pyridine, triethyamine,dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuranetc.) or without a solvent at a temperature of from 0° C. to 40° C., andthen by reacting the mixture of acid anhydride obtained with acorresponding alcohol in an inert organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.), at atemperature of from O° C. to 40° C.; and

[0197] (3) the method using a condensing agent (e.g.,1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[(dimethylamino)propyl]cabodiimide (EDC), 2-chloro-1-methypyridinium iodide etc.) may becarried out, for example, by reacting a carboxylic acid with acorresponding alcohol using a condensing agent in the presence orabsence of a tertiary amine (e.g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent(e.g., chloroform, methylene chloride, dimethyl formamide, diethyl etheretc.) or without a solvent at a temperature of from 0° C. to 40° C.

[0198] The formation of an amide may be accomplished by the samereactions as described above, except the corresponding alcohol isreplaced by a corresponding amine.

[0199] The reactions (1), (2) and (3) hereinbefore described may bepreferably carried out in an atmosphere of inert gas (e.g., argon,nitrogen etc.) under anhydrous conditions.

[0200] The compounds of the formula (III) may be prepared by the seriesof reactions depicted in the following Scheme A.

[0201] In the Scheme A,

[0202] R^(p) is t-butyl or benzyloxycarbonyl,

[0203] X¹⁰, X²⁰ and X³⁰ each independently, is halogen,

[0204] Ms is methaneosulfonic acid,

[0205] A₀₀ is bond, C1-3 alkylene, oxy-(C1-3) alkylene,thio-(C1-3)alkylene, C2-7 alkenylene, C2-7 alkenylene substituted bycarboxy or C1-4 alkoxycarbonyl, and the other symbols have the samemeaning as hereinbefore described.

[0206] The reactions in the scheme hereinbefore depicted may be carriedout by methods known per se. The compounds of the formulae (II), (IV),(V) and (VI) used as starting materials in this scheme are known per seor may be easily prepared by methods known per se.

[0207] Other starting materials and each of the reagents are known perse or may be prepared by known methods.

[0208] In each reaction in the present specification, products may bepurified in a conventional manner. For example, purification may becarried out by distillation at atmospheric or reduced pressure, highperformance liquid chromatography, thin layer chromatography or columnchromatography using silica gel or magnesium silicate, washing orrecrystallization. Purification may be carried out after each reaction,or after a series of reactions.

[0209] Physiological Effects

[0210] As mentioned above, it is understood that LTB₄ antagonist isuseful as an anti-inflammatory and anti-allergic agent.

[0211] Therefore, compounds of the present invention of formulas (IA)and (IB), having LTB₄ antagonistic activity, may be used for thetreatment of an animal, preferably a human, as an anti-inflammatory andanti-allergic agent.

[0212] It is known that an LTB₄ antagonist is also useful for theprevention and/or treatment of various diseases in animals, includinghumans. These diseases include rheumatoid arthritis, inflammatory boweldiseases, psoriasis, nonsteroidal anti-inflammatory agent-inducedstomach diseases, adult respiratory distress syndrome, cardiacinfarction, allergic rhinitis, hemodialysis-induced neutropenia andanaphase asthma.

[0213] The compounds of the formula (IB) also have inhibitory activityon phospholipase and inhibitory activity on trypsin in animals,including humans. Therefore compounds of formula (IB) are useful for theprevention and/or the treatment of various inflammatory, allergicdiseases, disseminated intravascular coagulation, pancreatitis, severityin pancreatitis and multiple organ failure in animals, preferablyhumans.

[0214] Toxicity

[0215] It is confirmed that the toxicity of the active ingredients andnon-toxic salts thereof and non-toxic acid addition salts thereof in thepresent invention is very weak. For example, LD₅₀ of Compound 1 was 117mg/kg when administered intravenously to male mice. Accordingly, theactive substances in the present invention may be considered to besufficiently safe and suitable for pharmaceutical use.

[0216] For the purpose hereinbefore described, the active ingredient inthe present invention and non-toxic salts thereof and non-toxic acidaddition salts thereof may be normally administered systemically orpartially, usually by oral or parenteral administration.

[0217] The doses to be administered are determined depending upon age,weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment, etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, or between 100μg and 100 mg, by parenteral administration (preferably, intravenously)up to several times per day. As mentioned above, the doses to be useddepend upon various conditions. Therefore, there are cases in whichdoses lower than or greater than the ranges specified above may be used.

[0218] Compounds of the present invention are administered in the formof solid compositions, liquid compositions or other compositions fororal administration, and as injections, liniments or suppositories,etc., for parenteral administration.

[0219] Solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders, and granules.

[0220] In such compositions, at least one of the active compounds isadmixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.).

[0221] These compositions may also comprise, as in normal practice,additional substances other than inert diluents: e.g., lubricatingagents (such as magnesium stearate, etc.), disintegrating agents (suchas cellulose calcium glycolate, etc.), assisting agents for dissolving(such as arginine, glutamic acid, asparaginic acid, etc.) andstabilizers (human serum albumin, lactose, etc.).

[0222] The tablets or pills may, if desired, be coated with a film ofgastric or enteric material (such as sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethyl cellulose phthalate, etc.).

[0223] Capsules include hard capsules and soft capsules.

[0224] Liquid compositions for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

[0225] These liquid compositions may comprise inert diluents commonlyused in the art (purified water, ethanol, etc.).

[0226] Besides inert diluents, such compositions may also compriseadjuvants (such as wetting agents, suspending agents, etc.), sweeteningagents, flavoring agents and preserving agents.

[0227] Other compositions for oral administration include spraycompositions, which may be prepared by known methods and which compriseone or more of the active compound(s). Spray compositions may compriseadditional substances other than inert diluents: e.g. stabilizing agents(sodium sulfate, etc.), isotonic stabilizing agents (sodium chloride,sodium citrate, citric acid, etc.). For preparation of such spraycompositions, for example, the method described in the U.S. Pat. No.2,868,691 or No. 3,095,355 may be used.

[0228] Injections for parenteral administration include sterile aqueousor non-aqueous solutions, suspensions and emulsions.

[0229] In such compositions, one or more of active compound(s) is or areadmixed with at least one of inert aqueous diluent(s) (distilled waterfor injection, physiological salt solution, etc.) or inert non-aqueousdiluent(s) (propylene glycol, polyethylene glycol, olive oil, ethanol,POLYSORBATE80 (registered trademark) etc.).

[0230] Injections may comprise furthermore assisting agents such aspreserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agents (such as human serum albumine, lactose, etc.)and assisting agents for dissolving (arginine, glutamic acid,asparaginic acid, polyvinylpyrrolidone, etc.).

[0231] Usually, they may be sterilized by filtration (abacteria-retaining filter etc), by incorporation of sterilizing agentsin the compositions or by irradiation, or after treated, they may alsomanufactured in the form of sterile solid compositions, for example, byfreeze-drying, which may be dissolved in sterile water or some othersterile diluent(s) for injection immediately before used, and which maybe used.

EXAMPLE

[0232] The following Reference Examples and Examples illustrarte thepresent invention.

[0233] The solvents in parentheses show the developing or elutingsolvents used in chromatographic separations and the solvent ratios usedare by volume.

Example 1 (A)

[0234] Binding Inhibition Against ³H-LTB₄ on the Human PolymorphonuclearLeukocyte (PMN)

[0235] 0.049 ml Hanks balanced salt solution (HBSS), 0.001 ml testcompound and 0.05 ml ³H-LTB₄ (4 nM) were added to polypropylene tubesand mixed. The reaction was started by addition of a thoroughly mixedPMN cell suspension (1.6×10⁶ cells), followed by incubation at 0° C. for20 min. The reaction was terminated by the addition of ice-cold HBSS(2.5 ml). PMNs were harvested by vacuum filtration through Whatman GF/Cglass fiber filters on a Brandel cell harvester (BRANDEL, M-24R). Thefilters were then washed 2 times to remove free ³H-LTB₄ with 2.5 ml ofthe ice-cold PBS (−) solution. The filters were transferred to eachvial, and equilibrated after adding 8 ml ACS II cocktail (Amersham). Theradioactivity was measured by liquid scintillation counter (Aloka,LSC-5100).

[0236] Specific binding of ³H-LTB₄ to the LTB₄ receptor was defined astotal binding minus nonspecific binding. Nonspecific binding was theamount of ³H-LTB₄ binding in the presence of 1.5 μM LTB₄ instead of thetest compound. The inhibitory effect of test compound was calculatedfrom the following equation.

The percentage of inhibition (%)=100−(B ₁ /B ₀×100)

[0237] B₁: Specific ³H-LTB₄ binding in presence of test compound

[0238] B₀: Specific ³H-LTB₄ binding in absence of test compound

[0239] Results

[0240] The results are shown in the following Table 17. TABLE 17European Patent Publication No. 588655 binding activity Compound No.Compound (Example No.) (%) 1 1 (i) 91.5 2 1 (m) 76.6 3 1 (p) 75.0 4 1(aa) 63.7 5 1 (ii) 94.3 6 1 (pp) 71.6 7 1 (qq) 78.0 8 1 (hhh) 82.7 9 1(lll) 91.6 10 1 (mmm) 86.5 11 2 (g) 76.8 12 2 (p) 95.2 13 2 (u) 100.2 142 (w) 96.5 15 2 (cc) 89.1 16 2 (gg) 83.6 17 2 (kk) 93.9 18 3 (f) 87.0 194 74.0 20 4 (a) 83.5 21 5 (r) 90.8 22 5 (w) 89.7 23 5 (ff) 78.0 24European Patent Publication 61.2 No. 656349 Example 1 (b)

[0241] The structure of compounds used in the present invention areshown below.

Example 1 (B)

[0242] The compounds of the formula (IB), of the present invention havean antagonistic activity on LTB₄. The results which are measured bymethod as hereinbefore described in Example 1 (A), are shown thefollowing Table 18. TABLE 18 binding activity Compound (Example No.) (%)2 79.7 2 (a) 92.0 2 (b) 97.9 2 (c) 103.2 2 (d) 99.3 2 (e) 94.5 2 (f)91.8 2 (g) 89.6 2 (h) 85.4 2 (i) 69.6 2 (j) 55.4 2 (k) 97.7 2 (l) 81.0 2(m) 89.2 2 (n) 82.8 2 (o) 85.8 2 (p) 95.2 2 (q) 98.0 2 (r) 80.1 2 (s)83.0 2 (t) 51.5 2 (u) 67.6 2 (v) 92.0 2 (w) 76.7 2 (x) 94.1 2 (y) 85.5 2(z) 92.8 2 (aa) 94.4 2 (bb) 87.3 2 (cc) 76.7 2 (dd) 50.8 2 (ee) 65.3 2(ff) 82.4 3 96.8 4 73.1 4 (a) 52.0 5 89.7 5 (a) 62.5 5 (b) 90.2 6 67.8

Example 1 (C)

[0243] Inhibitory Activity on Phospholipase A₂ and on Trypsin

[0244] It has been confirmed that compounds of formula (IB) of thepresent invention have inhibitory activities on phospholipaseA₂ (PLA₂)and on trypsin.

[0245] For example, in laboratory tests the following results wereobtained.

[0246] Method

[0247] (1) Inhibitory Activity on PLA₂

[0248] A reaction solution including 50 mM tris-HCl buffer (pH7.5, 874μl; containing 100 mM sodium chloride, 1 mM EDTA), 1M calciumchloride (6μl), 1% bovine serum albumin (10 μl) and 2.5 mM 10PY-PC (10 μl), wasprepared. To the solution were added a test compound in variousconcentration or water (50 μl), and a solution of 10 mU/ml PLA₂ (derivedfrom hog pancreas) (50 μl). The appearance of fluorescence was measured(Ex=345 nm, Em=396 nm). Percentage (%) of the strength of fluorescencein the presence of a test compound was calculated when the strength ofthat in the absence thereof was regarded as 100%, and therefrom IC₅₀value was calculated. The results are shown in the following Table19.

[0249] (2) Inhibitory Activity on Trypsin

[0250] To a mixture of a 0.2 M HEPES•sodium hydroxide buffer solution(pH 8.0, 100 μl) and distilled water (640 μl), were added a testcompound in various concentration or water (10 μl), and a solution of 80mU/ml trypsin (derived from bovine pancreas) (50 μl) and then themixture was preincubated for one minute at 30° C. To the solution thusobtained was added 2.5 mM BAPNA (200 μl) and the mixture was incubatedat 30° C. The absorbance at 405 nm was measured. Percentage (%) of theabsorbance in the presence of a test compound was calculated when theabsorbance in the absence thereof was regarded as 100%, and therefromIC₅₀ value was calculated. The results are shown in the following Table19. TABLE 19 inhibitory activity inhibitory activity Compound on PLA₂ ontrypsin (Example No.) IC₅₀ (μM) IC₅₀ (μM) 2 — 0.19 2 (a) 2.6 0.4 2 (b)3.8 0.56 2 (c) 8.1 0.26 2 (d) 8.7 0.14 2 (e) 8.5 0.34 2 (f) 70 0.10 2(g) 53 0.16 2 (h) 11 0.15 2 (i) 59 0.14 2 (j) — 0.12 2 (k) 20 0.10 2 (l)94 0.12 2 (m) 18 0.17 2 (n) 10 0.16 2 (o) 12 0.14 2 (p) 29 0.13 2 (q) 340.16 2 (r) 46 0.16 2 (s) 44 0.16 3 4.7 0.12 4 41 0.16 4 (a) — 0.14 5 —0.13 5 (a) — 0.15 6 4.5 0.17

[0251] In the methods hereinbefore described,

[0252] 10PY-PC represents3′-palmitoyl-2-(1-pyrenedecanoyl)-L-(α-phosphatidycholine,

[0253] HEPES represents 4-2-hydroxyethyl)-1-piperazineethanesulfonicacid, and

[0254] BAPNA represents α-N-benzoyl-DL-arginine-p-nitroanilidehydrochloride.

[0255] Preparation of New Compounds

[0256] The following Reference Examples and Examples illustrate thepreparation of new compounds of formula (IB).

Reference Examples 1

[0257]N-(2-Propenyl)-N-ethoxycarbonylmethyl-4-benzyloxycarbonylphenoxyacetamide.

[0258] A solution of 4-benzyloxycarbonylphenoxyacetic acid (4.29 g) inthionyl chloride (10 ml) was refluxed for 15 min. After an excess amountof solvent was distilled off, product was dissolved in dichloromethane.And this solution was added dropwise to a solution ofN-(2-propenyl)-N-ethoxycarbonylmethylamine (2.14 g) in pyridine undercooling with ice. After the solution was stirred for 30 min at roomtemperature, the solution was poured into ice water. The mixture wasextracted with ethyl acetate. The extract was washed with a solution of1N hydrochloric acid, water and a saturated aqueous solution of sodiumchloride, successively, and then evaporated. The residue was thenpurified by silica gel column chromatograhy to obtain the title compound(5.96 g) having the following physical data:

[0259] TLC:Rf 0.43 (hexane:ethyl acetate=3:2)

Reference Example 2

[0260] N-(2-Propenyl)-N-ethoxycarbonylmethyl-4-carboxyphenoxyacetamide

[0261] Methanesulfonic acid (28 ml) was added to the compound preparedin Reference Example 1 (5.69 g) under cooling at 0° C. After reaction,the solution was stirred for one hour at room temperature, poured intoice water and extracted with ethyl acetate. The organic layer was washedwith water, and a saturated aqueous solution of sodium chloride,successively, and then evaporated. The residue was purified by silicagel column chromatography to obtain the title compound (4.31 g) havingthe following physical data.

[0262] TLC:Rf 0.35 (hexane:ethyl acetate=1:1)

Example 2

[0263]N-(2-propenyl)-N-ethoxycarbonylmethyl-4-(4-amidinophenoxycarbonyl)phenoxyacetamideacetate

[0264] To a pyridine solution of amidinophenol (1.72 g) and the compoundprepared in Reference Example 2 (3.21 g) was added DCC (3.09 g) andstirred overnight at room temperature. The reaction solution wasfiltered and the filtrate was evaporated. The residue was purified bysilica gel column chromatography and was formed into acetate by aconventional manner to obtain the title compound having the followingphysical data.

[0265] TLC:Rf 0.41 (chloroform:methanol:acetic acid=10:2:1),

[0266] NMR (CD₃OD): δ 8.14(2H, d, J=9.0 Hz), 7.90(2H, d, J=9.0 Hz),7.49(2H, d, J=9.0 Hz), 7.08(2H, d, J=9.0 Hz), 5.68-6.07(1H, m),5.17-5.37(2H, m), 4.93 and 5.02(2H, s, ratio=7:10), 4.03-4.28(6H, m),1.26 and 1.29(3H, t, J=7.0 Hz).

Example 2 (a)˜2 (ff)

[0267] By the same procedure as Reference Examples 1-2 and Example 2,the compound having the following physical data was obtained.

Example 2 (a)

[0268]

[0269] TLC:Rf 0.57 (chloroform:methanol:acetic acid=10:2:1),

[0270] NMR (CD₃OD): δ 2.60(2H, t, J=8.0 Hz), 2.98(2H, t, J=8.0 Hz),5.17(2H, s), 6.99-7.02(2H, m), 7.09-7.16(5H, m), 7.30(5H, s), 7.38(1H,d, J=9.0Hz), 7.43(1H, s), 7.48(2H, d, J=8.0 Hz), 7.98(2H, d, J=8.0 Hz).

Example 2 (b)

[0271]

[0272] TLC:Rf 0.60 (chloroform:methanol:acetic acid=10:2:1),

[0273] NMR (CD₃OD): δ 2.41(2H, t, J=7.0 Hz), 3.00(2H, t, J=7.0 Hz),4.69(2H, s), 5.23(2H, s), 7.09-7.42(14H, m), 7.43(2H, d, J=8.0 Hz),7.98(2H, d, J=8.0 Hz).

Example 2 (c)

[0274]

[0275] TLC:Rf 0.53 (chloroform:methanol:acetic acid=10:2:1),

[0276] NMR (CD₃OD): δ 8.0(2H, d, J=8.0 Hz), 7.50(2H, d, J=8.0 Hz),7.46(1H, s), 7.40(1H, d, J=8.0 Hz), 7.24(5H, s), 7.12(1H, s), 7.10(1H,d, J=8.0 Hz), 4.61(2H, s), 4.22(2H, q, J=8.0 Hz), 3.00(2H, t, J=9.0 Hz),2.61(2H, t, J=9.0 Hz), 1.30(3H, t, J=8.0 Hz).

Example 2 (d)

[0277]

[0278] TLC:Rf 0.45 (chloroform:methanol:acetic acid=10:2:1),

[0279] NMR (CD₃OD): δ 8.00(2H, d, J=8 Hz), 7.80(1H, d, J=16 Hz),7.75(2H, d, J=8 Hz), 7.50(2H, d, J=8 Hz), 7.35(2H, d, J=8 Hz),7.30-7.20(5H, m), 6.70(1H, d, J=16 Hz), 4.65(2H, s), 4.25(2H, q, J=7Hz), 1.30(3H, t, J=7 Hz).

Example 2 (e)

[0280]

[0281] TLC:Rf 0.45 (chloroform:methanol:acetic acid=10:2:1),

[0282] NMR (CD₃OD): δ 1.30(3H, t, J=7.0 Hz), 2.18(3H, s), 4.31(2H, q,J=7.0 Hz), 4.77(2H, m), 5.02(1H, t, J=4.0 Hz), 7.39-7.61(8H, m),7.89(2H, d, J=9.0 Hz), 8.02(2H, d, J=9.0 Hz), 8.22(2H, d, J=9.0 Hz).

Example 2 (f)

[0283]

[0284] TLC:Rf 0.43 (chloroform:methanol:acetic acid=10:2:1),

[0285] NMR (CD₃OD): δ 8.00-7.80(7H, m), 7.50(2H, d, J=8.5 Hz), 6.90(1H,d, J=16 Hz), 4.60(1H, dd, J=4.5, 4.5 Hz), 4.20(2H, q, J=6.5 Hz),4.15(2H, q, J=6.5 Hz), 2.50(2H, t, J=7.5 Hz), 2.30(1H, m), 2.10(1H, m),1.30(3H, t, J=6.5 Hz), 1.25(3H, t, J=6.5 Hz).

Example 2 (g)

[0286]

[0287] TLC:Rf 0.46 (chloroform:methanol:acetic acid=10:2:1),

[0288] NMR (CD₃OD): δ 8.00-7.90(5H, m), 7.65(2H, d, J=8 Hz), 7.50(2H, d,J=8 Hz), 4.65(1H, dd, J=4.5, 4.5 Hz), 4.20(2H, q, J=6.5 Hz), 4.15(2H, q,J=6.5 Hz), 2.50(2H, t, J=7.5 Hz), 2.30(1H, m), 2.25(3H, m), 2.10(1H, m),1.30(3H, t, J=6.5 Hz), 1.25(3H, t, J=6.5 Hz).

Example 2 (h)

[0289]

[0290] TLC:Rf 0.48 (chloroform:methanol:acetic acid=15:2:1),

[0291] NMR (CD₃OD): δ 8.24(2H, d, J=8.5 Hz), 7.95(2H, d, J=8.5 Hz),7.62(2H, d, J=8.0 Hz), 7.55(2H, d, J=8.0 Hz), 7.35(1H, s), 6.85(1H, dt,J=7.5, 15.0 Hz), 5.93(1H, d, J=15.0 Hz), 4.28(4H, q, J=7.5 Hz), 4.18(2H,d, J=7.5 Hz), 3.23(2H, d, J=7.5 Hz), 2.14(3H, s), 1.26(6H, t, J=7.5 Hz),1.23(3H, t, J=7.5 Hz).

Example 2 (i)

[0292]

[0293] TLC:Rf 0.43 (chloroform:methanol:acetic acid=10:2:1),

[0294] NMR (CD₃OD): δ 8.24 and 8.26(2H, d, J=9.0 Hz), 7.81(1H, d, J=18.0Hz), 7.75(2H, d, J=9.0 Hz), 7.58 and 7.66(2H, d, J=9.0 Hz), 7.37(2H, d,J=9.0 Hz), 6.73(1H, d, J=18.0 Hz), 5.77-5.96(1H, m), 5.22-5.34(2H, m),4.12-4.28(4H, m), 3.96-4.00(2H, m), 1.20 and 1.30(3H, t, J=7.0 Hz).

Example 2 (j)

[0295]

[0296] TLC:Rf 0.44 (chloroform:methanol:acetic acid=10:2:1),

[0297] NMR (CD₃OD): δ 8.18(2H, d, J=9.0 Hz), 7.90(2H, d, J=9.0 Hz),7.50(2H, d, J=9.0 Hz), 7.17(2H, d, J=9.0 Hz), 4.70(2H, s), 4.55(1H, dd,J=9.5, 5.0 Hz), 4.18(2H, q, J=7.0 Hz), 4.11(2H, q, J=7.0 Hz), 2.40(2H,t, J=7.0 Hz), 1.97-2.32(2H, m), 1.27(3H, t, J=7.0 Hz), 1.23(3H, t, J=7.0Hz).

Example 2 (k)

[0298]

[0299] TLC:Rf 0.48 (chloroform:methanol:acetic acid=15:2:1),

[0300] NMR (CD₃OD): δ 8.22(2H, d, J=8.0 Hz), 7.92(2H, d, J=8.0 Hz),7.60(2H, d, J=8.0 Hz), 7.56(2H, d, J=8.0 Hz), 7.37(1H, brs), 4.27(4H, q,J=7.5 Hz), 4.13(2H, q, J=7.5 Hz), 3.47(2H, s), 2.16(3H, s), 1.25(6H, t,J=7.5 Hz), 1.22(3H, t, J=7.5 Hz).

Example 2 (l)

[0301]

[0302] TLC:Rf 0.49 (chloroform:methanol:acetic acid=10:2:1),

[0303] NMR (CD₃OD): δ 7.98(1H, s), 7.90(2H, d, J=9.0 Hz), 7.58(4H, m),7.48(2H, d, J=9.0 Hz), 5.78-5.96(1H, m), 5.23-5.32(2H, m), 4.22(2H, q,J=7.0 Hz), 4.20(2H, s), 3.98-4.03(2H, m), 2.24(3H, s), 1.30(3H, t, J=7.0Hz).

Example 2 (m)

[0304]

[0305] TLC:Rf 0.38 (chloroform:methanol:acetic acid=10:1:1),

[0306] NMR (CD₃OD): δ 8.20(2H, d, J=8.4 Hz), 7.92(2H, d, J=8.8 Hz),7.74(2H, d, J=8.4 Hz), 7.55(2H, d, J=8.8 Hz) 7.25(3H, m), 6.32(1H, d,J=14.6 Hz), 4.55(1H, m), 4.20(2H, q, J=7.2 Hz), 4.14(2H, q, J=7.0 Hz),2.72(3H, s), 2.45(2H, t, J=7.4 Hz), 2.36-1.90(2H, m), 1.29(3H, t, J=7.2Hz), 1.25(3H, t, J=7.0 Hz).

Example 2 (n)

[0307]

[0308] TLC:Rf 0.39 (chloroform:methanol:acetic acid=10:1:1),

[0309] NMR (CD₃OD): δ 8.18(2H, d, J=8.4 Hz), 7.92(2H, d, J=8.8 Hz),7.73(2H, d, J=8.4 Hz), 7.53(2H, d, J=8.8 Hz), 7.50-7.15(2H, m), 7.05(1H,d, J=14.5 Hz), 6.75-6.55(1H, m), 6.03-5.81(1H, m), 5.32-5.14(2H, m),4.20(2H, q, J=7.2 Hz), 4.30-4.10(4H, m), 1.94(3H, s), 1.28(3H, t, J=7.2Hz).

Example 2 (o)

[0310]

[0311] TLC:Rf 0.50 (chloroform:methanol:acetic acid=10:2:1),

[0312] NMR (CD₃OD): δ 8.20(2H, d, J=8.5 Hz), 7.90(2H, d, J=11.5 Hz),7.60(2H, d, J=8.5 Hz), 7.55(2H, d, J=11.5 Hz), 7.35(1H, br.s), 5.70(1H,m), 5.15(2H, m), 4.25(4H, q, J=7 Hz), 3.10(2H, d, J=7 Hz), 2.15(3H, s),1.95(3H, s), 1.25(6H, t, J=7HZ).

Example 2 (p)

[0313]

[0314] TLC:Rf 0.50 (chloroform:methanol:acetic acid=10:1:1),

[0315] NMR (CD₃OD): δ 7.94(2H, d, J=8.0 Hz), 7.89(2H, d, J=8.5 Hz),7.72(2H, d, J=8.5 Hz), 7.44(2H, d, J=8.0 Hz), 6.49(1H, s), 4.64(1H, m),4.23(2H, q, J=7.5 Hz), 4.14(2H, q, J=7.0 Hz), 2.74(3H, s), 2.66(3H, s),2.52(2H, t, J=7.0 Hz), 2.32(2H, m), 2.14(2H, m), 1.30(3H, t, J=7.0 Hz),1.25(3H, t, J=7.5 Hz).

Example 2 (q)

[0316]

[0317] TLC:Rf 0.50 (chloroform:methanol:acetic acid=10:1:1),

[0318] NMR (CD₃OD): δ 7.89(2H, d, J=8.8 Hz), 7.73(2H, d, J=8.4 Hz),7.56(2H, d, J=8.4 Hz), 7.44(2H, d, J=8.8 Hz), 6.49(1H, s), 5.88(1H, m),5.35-5.20(2H, m), 4.30-4.10(4H, m), 4.00(2H, m), 2.65(3H, s), 1.93(3H,s), 1.31(3H, t, J=7.2 Hz).

Example 2 (r)

[0319]

[0320] TLC:Rf 0.46 (chloroform:methanol:acetic acid=10:2:1),

[0321] NMR (CD₃OD): δ 8.18(2H, d, J=9.0 Hz), 7.93(2H, d, J=9.0 Hz),7.82(2H, d, J=9.0 Hz), 7.80(1H, s), 7.52(2H, d, J=9.0 Hz), 4.66(1H, dd,J=8.5 Hz,4.0 Hz), 4.33(2H, q, J=7.0 Hz), 4.20(2H, q, J=7.0 Hz), 4.12(2H,q, J=7.0 Hz), 2.39(2H, t, J=7.0 Hz), 2.11-2.31(1H, m), 1.82-2.00(1H, m),1.36(3H, t, J=7.0 Hz), 1.24(3H, t, J=7.0 Hz), 1.21(3H, t, J=7.0 Hz).

Example 2 (s)

[0322]

[0323] TLC:Rf 0.43 (chloroform:methanol:acetic acid=10:2:1),

[0324] NMR (CD₃OD): δ 8.20 and 8.22(2H, d, J=8.0 Hz), 7.92(2H, d, J=9.0Hz), 7.75-7.90(1.6H, m), 7.64(1H, d, J=8.0 Hz), 7.54(2H, d, J=9.0 Hz),7.18 and 7.26(0.4H, m),5.54-5.72(0.4H, m), 5.10-5.31(2H, m),4.17-4.40(6H, m), 3.98(2H, br), 1.08-1.38(6H, m).

Example 2 (t)

[0325]

[0326] TLC:Rf 0.15 (chloroform:acetic acid:H₂O=3:1:1),

[0327] NMR (CD₃OD): δ 8.23(2H, d, J=8 Hz), 7.93(2H, d, J=8 Hz), 7.58(2H,d, J=8 Hz), 7.53(2H, d, J=8 Hz), 6.80(1H, bs), 6.10-5.90(1H, b),5.35-5.20(2H, m), 4.25-4.00(4H, m), 3.68-3.45(2H, m), 3.25-3.00(2H, m),2.88(6H, s), 2.69(3H, s), 2.15(3H, s), 1.96(3H, s).

Example 2 (u)

[0328]

[0329] TLC:Rf 0.46 (chloroform:methanol:acetic acid=10:2:1),

[0330] NMR (CD₃OD): δ 8.18(2H, d, J=9.0 Hz), 7.93(2H, d, J=9.0 Hz),7.82(2H, d, J=9.0 Hz), 7.80(1H, s), 7.52(2H, d, J=9.0 Hz), 4.66(1H, dd,J=8.5 Hz,4.0 Hz), 4.33(2H, q, J=7.0 Hz), 4.20(2H, q, J=7.0 Hz), 4.12(2H,q, J=7.0 Hz), 2.39(2H, t, J=7.0 Hz), 2.11-2.31(1H, m), 1.82-2.00(1H, m),1.36(3H, t, J=7.0 Hz), 1.24(3H, t, J=7.0 Hz), 1.21 (3H, t, J=7.0 Hz).

Example 2 (v)

[0331]

[0332] TLC:Rf 0.22 (chloroform:methanol:acetic acid=10:2:1),

[0333] NMR (CD₃OD): δ 8.21(2H, d, J=8.0 Hz), 7.95(2H, d, J=8.0 Hz),7.89(2H, d, J=8.0 Hz), 7.59(2H, d, J=8.0 z), 7.55(2H, d, J=8.0 Hz),7.43(2H, d, J=8.0 Hz), 6.78(1H, s), 6.15-5.80(1H, m), 5.47-5.28(2H, m),4.42(2H, s), 4.25(2H, d, J=5.0 Hz), 2.68(3H, S, CH₃SO₃H), 2.18(3H, s).

Example 2 (w)

[0334]

[0335] TLC:Rf 0.27 (chloroform:methanol:acetic acid=10:2:1),

[0336] NMR (CD₃OD): δ 8.20(2H, d, J=8 Hz), 7.91(2H, d, J=8 Hz), 7.57(2H,d, J=8 Hz), 7.53(21, d, J=8 Hz), 6.73(1H, s), 5,8-6.0(1H, br),5.2-5.35(2H, m), 4.8-4.9(1H, m), 4.0-4.3(8H, m), 2.12(3H, s), 1.91(3H,s)1.27(6H, t, J=7 Hz).

Example 2 (x)

[0337]

[0338] TLC:Rf 0.25 (chloroform:methanol:acetic acid=10:2:1),

[0339] NMR (CD₃OD): δ 8.22(2H, d, J=8 Hz), 7.91(2H, d, J=8 Hz), 7.52 and7.67(4H, d, J=8 Hz, rotamer), 6.65 and 6.78(1H, s, rotamer), 5.6-6.0(3H,br), 5.0-5.3(6H, m), 3.9-4.4(8H, m), 2.11 and 2.16(3H, s, rotamer),1.92(3H, s).

Example 2 (y)

[0340]

[0341] TLC:Rf 0.41 (chloroform:methanol:acetic acid=20:2:1),

[0342] NMR (CD₃OD): δ 8.22(2H, d, J=8.0 Hz), 7.94(2H, d, J=8.0 Hz),7.55(4H, t, J=7.5 Hz), 6.71(1H, brs), 5.20-4.90(1H, m), 4.40-4.00(6H,m), 2.20-2.00(3H, m), 1.95-1.50(3H, m), 1.30(6H, t, J=7.5 Hz),1.10-0.80(6H, m).

Example 2 (z)

[0343]

[0344] TLC:Rf 0.40 (chloroform:methanol:acetic acid=20:2:1),

[0345] NMR (CD₃OD): δ 8.21(2H, d, J=8.5 Hz), 7.95(2H, d, J=8.5 Hz),7.57(4H, t, J=8.0 Hz), 6.62(1H, s), 4.15(2H, q, J=7.0 Hz), 3.80-3.60(2H,m), 3.55-3.38(2H, m), 2.68(2H, t, J=7.5 Hz), 2.12(3H, s), 1.70-1.40(3H,m), 1.27(3H, t, J=7.5 Hz), 1.10-0.70(6H, m).

Example 2 (aa)

[0346]

[0347] TLC:Rf 0.55 (chloroform:methanol:acetic acid=10:2:1),

[0348] NMR (CD₃OD): δ 8.23(2H, d, J=8 Hz), 7.93(2H, d, J=8 Hz), 7.57(2H,d, J=8 Hz), 7.54(2H, d, J=8 Hz), 6.60(1H, s), 3.92-3.50(3H, m),2.70-2.55(2H, m), 2.13 and 2.11(3H, s), 1.93-1.00(10H, m).

Example 2 (bb)

[0349]

[0350] TLC:Rf 0.41 (chloroform:methanol:acetic acid=10:2:1),

[0351] NMR (CD₃OD): δ 8.21(2H, d, J=8 Hz), 7.92(2H, d, J=8 Hz),7.65-7.50(4H, m), 6.72 and 6.65(1H, s, rotamer), 4.2-4.1(4H, m),3.8-3.6(2H, br), 3.6-3.5(2H, br), 3.34(3H, s), 2.17(3H, s), 1.91(AcOH),1.35-1.15(3H, br).

Example 2 (cc)

[0352]

[0353] TLC:Rf 0.30 (chloroform:methanol:acetic acid=10:2:1),

[0354] NMR (CD₃OD): δ 8.21(2H, d, J=8 Hz), 7.92(2H, d, J=8 Hz),7.60-7.45(4H, m), 6.73 and 6.65(1H, s, rotamer), 4.5-4.3(1H, m),4.3-4.0(2H, br), 4.0-3.7(3H, m), 3.7-3.5(1H, br), 2.70(3H, s), 2.17 and2.10(3H, s, rotamer), 2.2-1.8(3H, m), 1.8-1.4(1H, m).

Example 2 (dd)

[0355]

[0356] TLC:Rf 0.10 (ethyl acetate:acetic acid:H₂O=3:1:1),

[0357] NMR (CD₃OD): δ 8.22(2H, d, J=8 Hz), 7.92(2H, d, J=8 Hz),7.7-7.4(4H, m), 6.70(1H, s), 4.5-4.0(3H, br), 3.6-3.4(2H, m),3.2-3.0(2H, m), 2.3-1.9(7H, br).

Example 2 (ee)

[0358]

[0359] TLC:Rf 0.43 (chloroform:methanol:acetic acid=3:1:1),

[0360] NMR (CD₃OD): δ 9.20(1H, br. s), 8.70(1H, br. s), 8.05-7.95(4H,m), 7.85(2H, d, J=9 Hz), 7.75(2H, J=8 Hz), 6.75(1H,m), 5.95(1H, m),5,30(2H, m), 4.20(4H, m), 2.75(3H, s, CH₃SO₃H), 2.20(3H, s).

Example 2 (ff)

[0361]

[0362] TLC:Rf 0.40 (chloroform:methanol:acetic acid=10:2:1),

[0363] NMR (CDCl₃): δ 8.02(1H, d, J=9 Hz), 7.90(1H, d, J=9 Hz), 7.64(1H,s), 7.50(1H, d, J=9 Hz), 7.40-7.00(1411, m), 6.95-6.80(2H, m),6.80-6.72(1H, m), 6.48(1H, d, J=9 Hz), 4.00-3.80(1H, m), 3.88(3H, s),3.70-3.30,(2H, m), 3.10-2.90(1H, m), 2.90-2.70(2H, m), 2.70-2.30(2H, m),2.30-2.00(2H, m), 1.00-1.24(1H, m).

Reference Example 3

[0364]2-(N-Benzyl-N-methylamino)-2-(4-t-butoxycarbonylphenylmethylimino)aceticAcid Ethyl Ester.

[0365] To a solution of 2-(N-benzyl-N-methylamino)-2-thioxoacetic acidethyl ester (4.98 g) in dichloromethane under cooling with ice, wasadded dropwise BF₄—Et₃O (72 ml). The reaction solution was stirred for30 min at room temperature and extracted with dichloromethane. Theextract was evaporated. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound having the followingthe physical data.

[0366] TLC:Rf 0.45 (hexane:ethyl acetate=3:1).

Reference Example 4

[0367] 2-(N-Benzyl-N-methylamino)-2-(4-carboxyphenylmethylimino)aceticAcid Ethyl Ester

[0368] To a solution of the compound prepared in Reference Example 3(3.77 g) in anisole (10 ml) under cooling with ice bath, was addedtrifluoroacetic acid (20 ml) and stirred for two hours at roomtemperature. The reaction solution was evaporated, neutralizied byadding 1N aqueous solution of sodium hydroxide, and extracted with ethylacetate. The extract was evaporated. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (1.87g) having the following physical data.

[0369] TLC:Rf 0.36 (hexane:ethyl acetate=1:2).

Example 3

[0370]2-[4-(4-Amidinophenoxycarbonyl)phenylmethylimino]-2-(N-benzyl-N-methylamino)aceticAcid Ethyl Ester Hydrochroride

[0371] By the same procedure as Example 2, the title compound having thefollowing physical data was obtained.

[0372] TLC:Rf 0.34 (chloroform:methanol:acetic acid=10:2:1),

[0373] NMR (CD₃OD): δ 1.26(3H, t, J=7.0 Hz), 2.88(3H, s), 4.36(2H, q,J=7.0 Hz), 4.49(2H, s), 4.50(2H, s), 7.27-7.35(5H, m), 7.48(2H, d, J=9.0Hz), 7.52(2H, d, J=9.0 Hz), 7.92(2H, d, J=9.0 Hz), 8.12(21H, d, J=9.0Hz).

Reference Example 5

[0374] Ethyl1-(3-phenylpropyl)-1-(4-benzyloxycarbonylphenylmethyl)phosphinate.

[0375] A solution of ethyl phenylpropylphosphinate (1.2 g) andtriethylamine (2.4 ml) in chloroform (30 ml) was cooled to 0° C., and asolution of trimethylsilylchloride (1.46 ml) and 4-bromomethylbenzoicacid benzyl ester (1.75 g) in chloroform (10 ml) was added thereof, andstirred at room temperature for 1.5 day. To the reaction mixture wasadded ice water and extracted with ethyl acetate. Organic layer waswashed with water and a saturated aqueous solution of sodium chloride,successively evaporated. The residue was purified by silica gel columnchromatography to give the title compound (900 mg).

Reference Example 6

[0376] Ethyl 1-(3-phenylpropyl)-1-(4-carboxyphenylmethyl)phosphinate

[0377] A mixture of the compound prepared in Reference Example 5 (900mg), palladium carbon (180 mg, 10%) and ethanol (20 ml) was stirred fortwo hours under an atmosphere of hydrogen at room temperature. Thereaction mixture was filtered. The filtrate was evaporated and the titlecompound (815mg) was obtained.

Example 4

[0378] Ethyl1-(4-amidinophenoxycarbonylphenylmethyl)-1-(3-phenylpropyl)phosphinateacetate

[0379] By the same procedure as Reference Example 5,6 and Example 2, thetitle compound (805 mg) having the following physical data was obtained.

[0380] TLC:Rf 0.62 (chloroform:methanol:acetic acid=10:2:1),

[0381] NMR (CD₃OD): δ 8.10(2H, d, J=8 Hz), 7.95(2H, d, J=9 Hz), 7.55(2H,d, J=9 Hz), 7.60-7.40(2H, m), 7.30-7.10(3H, m), 7.20(2H, d, J=8 Hz),4.00(2H, m), 3.40(2H, d, J=24 Hz), 2.70(2H, t, J=6.5 Hz), 2.00-1.60(4H,m), 1.30(3H, t,J=7.5 Hz).

Example 4(a)

[0382]

[0383] By the same procedure as Example 4, the compound having thefollowing physical data was obtained.

[0384] TLC:Rf 0.60 (chloroform:methanol:acetic acid=10:2:1),

[0385] NMR (CD₃OD): δ 1.36(6H, t, J=7.0 Hz), 4.15(4H, quin, J=7.0 Hz),6.68(1H, t, J=18.0 Hz), 7.54(2H, d, J=9.0 Hz), 7.56(1H, dd, J=23.0Hz,18.0 Hz), 7.82(2H, d, J=9.0 Hz), 7.93(2H, d, J=9.0 Hz), 8.22(2H, d,J=9.0 Hz).

Reference Example 7

[0386] 4-Phenylpiperidine-1-ylmethylbenzoic Acid Methyl Ester

[0387] A solution of 4-formylbenzoic acid (3.5 g) and 4-phenylpiperidine(6.9 g) in methanol (35 ml) was stirred for one hour at roomtemperature. After the solution was cooled with ice bath, sodiumborohydride (1.63 g) was added and the reaction solution was stirred.After the reaction finished, the reaction solution was poured into icewater and extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of sodium chloride,successively, dried over and evaporated. The residue was washed withmethanol to obtain the title compound (4.70 g).

Reference Example 8

[0388] 4-(4-Phenylpiperidine-1-ylmethyl)benzoic Acid

[0389] A solution of the compound prepared in Reference Example 7 (4.8g) in dioxane (50 ml) was cooled with ice bath and 2N aqueous solutionof sodium hydroxide (10 ml) was added thereof and stirred at 60° C. fortwo hours. The reaction mixture was cooled with ice bath and neutralizedby adding 2N hydrochloric acid. Depositing solid was fittered and washedwith water, ether successively, dried over. The title compound (4.29 g)was obtained.

Example 5

[0390] 4-(4-Phenylpiperidine-1-ylmethyl)benzoic Acid Amidinophenol Ester2 Hydrochloride

[0391] By the same procedure as Example 2, the title compound having thefollowing physical data was obtained.

[0392] TLC:Rf 0.33 (chloroform:methanol:acetic acid=5:1:1),

[0393] NMR (CD₃OD): δ 8.32(2H, d, J=8.0 Hz), 7.95(2H, d, J-8.8 Hz),7.88(2H, d, J=8.0 Hz), 7.55(2H, d, J=8.8 Hz), 7.28(5H, m), 4.52(2H, s),3.62(2H, br.d), 3.25(2H, br.d), 2.94(1H, m), 2.12(4H, m).

Example 5(a)-5(b)

[0394] By the same procedure as Reference Example 7,8 and Example 5, thecompounds having the following physical data were obtained.

Example 5 (a)

[0395]

[0396] TLC:Rf 0.3 (chloroform:methanol:acetic acid=50:10:1),

[0397] NMR (CD₃OD): δ 8.20(2H, d, J=8.0 Hz), 7.95(2H, d, J=8.0 Hz),7.81(1H, d, J=2.0 Hz), 7.79(1H, d, J=2.0 Hz), 7.69(5H, brs), 7.55(2H, d,J=8.5 Hz), 7.39(2H, d, J=8.5 Hz), 5.63(2H, s), 2.72(6H, s).

Example 5 (b)

[0398]

[0399] TLC:Rf 0.48 (chloroform:methanol:acetic acid=10:1:1),

[0400] NMR (CD₃OD+CDCl₃): δ 8.05(2H, d, J=8.4 Hz), 7.89(2H, d, J=8.8Hz), 7.71(1H, d, J=8.0 Hz), 7.46(2H, d, J=8.8 Hz), 7.40(1H, s),7.37-7.30(2H, m), 7.17(1H, d, J=8.0 Hz), 7.16(2H, d, J=8.4 Hz), 5.95(2H,s), 4.30(2H, q, J=7.4 Hz), 2.73(3H, s), 1.33(3H, t, J=7.4 Hz).

Reference Example 9

[0401] 4-(N-Benzyl-N-ethoxycarbonylaminomethyl)benzoic Acid Benzyl Ester

[0402] A solution of 4-(N-benzylaminomethyl)benzoic acid benzyl ester(5.21 g) and bromoacetic acid benzyl ester (1.7 ml) in DMF (10 ml) wasstirred for two hours at 80° C. and ice water was added thereto. Thereaction solution was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride,successively. The organic layer was dried over and evaporated. Theresidue was purified by silica gel column chromatography to obtain thetitle compound (2.26 g).

Reference Example 10

[0403] 4-(N-Benzyl-N-ethoxycarbonylaminomethyl)benzoic AcidHydrochloride

[0404] A mixture solution of the compound prepared in Reference Example9 (2.26 g), methanesufonic acid (10.5 ml), and anisole (25 ml) wasstirred for one hour at room temperature. To the reaction solution wasadded ice water and extracted with chloroform. The organic layer waswashed with water, a saturated aqueous solution of sodium chloride,dried over and evaporated. The residue was purified by silica gel columnchromatography to obtain amine. 4N hydrochloric acid-dioxane was addedto the amine and the mixture was evaporated to obtain the title compound(1.76 g).

Example 6

[0405] N-(4-(4-Amidino-phenoxycarbonyl)phenylmethyl)-N-benzylaminoaceticAcid Ethyl Ester 2 Hydrochroride

[0406] By the same prodedure as Example 2, the title compound having thefollowing physical data was obtained.

[0407] TLC:Rf 0.42 (chloroform:methanol:acetic acid=10:2:1),

[0408] NMR (CD₃OD): δ 8.25(2H, d, J=8 Hz), 7.90(2H, d, J=8 Hz), 7.60(2H,d, J=8 Hz), 7.50(2H, d, J=8 Hz), 7.40-7.20(5H, m), 4.15(2H, q, J=7 Hz),3.90(2H, s), 3.80(2H, s), 3.30(2H, s), 1.25(3H, t, J=7 Hz). FormulationExample I The following components were admixed in a conventional mannerand punched out to obtain 100 tables, each containing 100 mg of activeingredient. Compound number 1 10 g Cellulose calcium glycolate(disintegrating agent) 0.2 g Magnesium stearate (Lubricating agent) 0.1g Microcrystaline cellulose 1.7 g Formulation Example 2 The followingcomponents were admixed conventional method and punched out to obtain100 tables each containing 100 mg of active ingredient. Compound number2 1 g Cellulose calcium glycolate (disintegrating agent) 0.2 g Magnesiumstearate (Lubricating agent) 0.1 g Microcrystaline cellulose 1.7 gFormulation Example 3 The following components were admixed inconventional manner. The solution was sterilized conventional manner,placed 5 ml portions into 10 ml ampoules and obtained 100 ampoules eachcontaining 10 mg of the active ingredient. Compound number 1 1 g Citricacid 0.2 g distilled water 500 ml Formulation Example 4 The followingcomponents were admixed in conventional manner. The solution wassterilized in conventional manner, placed 5 ml portions into 10 mlampules to obtain 100 ampoules, each containing 10 mg of the activeingredient. Compound number 2 1 g Citric acid 0.2 g distilled water 500ml

[0409] TABLE 1

Preferable groups as R

[0410] TABLE 2

Preferable groups as R

[0411] TABLE 3

Preferable groups as R

[0412] TABLE 4

Preferable groups as R

[0413] TABLE 5

Preferable groups as R

[0414] TABLE 6

Preferable groups as R

[0415] TABLE 7

Preferable groups as R

[0416] TABLE 8

Preferable groups as R

[0417] TABLE 9

Preferable groups as R

[0418] TABLE 10

Preferable groups as R

[0419] TABLE 11

Preferable groups as R

[0420] TABLE 12

Preferable groups as R

[0421] TABLE 13

Preferable groups as R

[0422] TABLE 14

Preferable groups as R

[0423] TABLE 15

Preferable groups as R

[0424] TABLE 16

Preferable groups as R

[0425] Pharmaceutical compositions of the present invention can beprepared using one active ingredient or two or more active ingredients.

[0426] Salts and Acid-additon Salts

[0427] Compounds of the formulae (IA) and (IB) of the present inventionmay be converted into the corresponding salts and acid-addition salts byknown methods. Nontoxic and water-soluble salts are preferred.

[0428] Suitable salts include the salts of alkali metals (sodium,potassium etc.), alkaline-earth metal (calcium, magnesium etc.),ammonium salts, salts of pharmacoligically acceptable organic amines(tetramethyl ammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenetylamine, piperidine,monoethanolamine, diethanolamine, tris (hydroxymethyl)aminomethane,lysine, arginine, N-methyl-D-gulcane etc).

[0429] Suitable acid-addition salts include the salts with inorganicacids such as hydrochloric acid, and the salts with organic acids suchas acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalicacid, fumaric acid, maleic acid, citric acid, benzoic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, isethionic acid, glucuronic acid and gluconicacid. Preferred salts include the salts with acids such as hydrochloricacid, methanesulfonic acid, acetic acid and trifluoroacetic acid.

[0430] Preparation of Compounds

[0431] The compounds of the formula (IA) may be prepared by methodsknown per se, as defined in published applications EP-A-588655 andEP-A-656349. The formula (1B) compounds of the present invention may beprepared by forming an ester or amide bond between a compound of theformula (II):

[0432] (wherein the various symbols have the same meanings ashereinbefore defined) with a compound of the formula (III):

[0433] (wherein the various symbols have the same meanings ashereinbefore defined). The esterification reaction and the reaction toform an amide are known and can be carried out by known method, forexample:

[0434] (1) using an acid halide,

[0435] (2) using a mixed acid anhydride or

[0436] (3) using a condensing agent.

[0437] Esterification can be carried out, for example, as follows:

[0438] (1) the method using an acid halide may be carried out, forexample, by reacting a carboxylic acid with an acid halide (e.g., oxalylchloride, thionyl chloride etc.) in an inert organic solvent (e.g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) orwithout a solvent at from −20° C. to the reflux temperature of thesolvent, and then by reacting the acid halide obtained with acorresponding alcohol in the presence of a tertiary amine (e.g.,pyridine, triethylamine, diethylaniline, diethylaminopyridine etc.) inan inert organic solvent (e.g., chloroform, methylene chloride, diethylether, tetrahydrofuran etc.) at a temperature of from 0° C. to 40° C.;

[0439] (2) the method using a mixed acid anhydride may be carried out,for example, by reacting a carboxylic acid and an acid halide (e.g.,pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acidderivative (e.g., ethyl chloroformate, isobutyl chloroformate etc.) inthe presence of a tertiary amine (e.g., pyridine, triethyamine,dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuranetc.) or without a solvent at a temperature of from 0° C. to 40° C., andthen by reacting the mixture of acid anhydride obtained with acorresponding alcohol in an inert organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.), at atemperature of from 0° C. to 40° C.; and

[0440] (3) the method using a condensing agent (e.g.,1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[(dimethylamino)propyl]cabodiimide (EDC), 2-chloro-1-methypyridinium iodide etc.) may becarried out, for example, by reacting a carboxylic acid with acorresponding alcohol using a condensing agent in the presence orabsence of a tertiary amine (e.g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent(e.g., chloroform, methylene chloride, dimethyl formamide, diethyl etheretc.) or without a solvent at a temperature of from 0° C. to 40° C.

[0441] The formation of an amide may be accomplished by the samereactions as described above, except the corresponding alcohol isreplaced by a corresponding amine.

[0442] The reactions (1), (2) and (3) hereinbefore described may bepreferably carried out in an atmosphere of inert gas (e.g., argon,nitrogen etc.) under anhydrous conditions.

[0443] The compounds of the formula (III) may be prepared by the seriesof reactions depicted in the following Scheme A.

[0444] In the Scheme A,

[0445] RP is t-butyl or benzyloxycarbonyl,

[0446] X¹⁰, X²⁰ and X³⁰ each independently, is halogen,

[0447] Ms is methaneosulfonic acid,

[0448] A₀₀ is bond, C1-3 alkylene, oxy-(C1-3) alkylene,thio-(C1-3)alkylene, C2-7 alkenylene, C2-7 alkenylene substituted bycarboxy or C1-4 alkoxycarbonyl, and the other symbols have the samemeaning as hereinbefore described.

[0449] The reactions in the scheme hereinbefore depicted may be carriedout by methods known per se. The compounds of the formulae (II), (IV),(V) and (VI) used as starting materials in this scheme are known per seor may be easily prepared by methods known per se.

[0450] Other starting materials and each of the reagents are known perse or may be prepared by known methods.

[0451] In each reaction in the present specification, products may bepurified in a conventional manner. For example, purification may becarried out by distillation at atmospheric or reduced pressure, highperformance liquid chromatography, thin layer chromatography or columnchromatography using silica gel or magnesium silicate, washing orrecrystallization. Purification may be carried out after each reaction,or after a series of reactions.

[0452] Physiological Effects

[0453] As mentioned above, it is understood that LTB₄ antagonist isuseful as an anti-inflammatory and anti-allergic agent.

[0454] Therefore, compounds of the present invention of formulas (IA)and (IB), having LTB₄ antagonistic activity, may be used for thetreatment of an animal, preferably a human, as an anti-inflammatory andanti-allergic agent.

[0455] It is known that an LTB₄ antagonist is also useful for theprevention and/or treatment of various diseases in animals, includinghumans. These diseases include rheumatoid arthritis, inflammatory boweldiseases, psoriasis, nonsteroidal anti-inflammatory agent-inducedstomach diseases, adult respiratory distress syndrome, cardiacinfarction, allergic rhinitis, hemodialysis-induced neutropenia andanaphase asthma.

[0456] The compounds of the formula (IB) also have inhibitory activityon phospholipase and inhibitory activity on trypsin in animals,including humans. Therefore compounds of formula (IB) are useful for theprevention and/or the treatment of various inflammatory, allergicdiseases, disseminated intravascular coagulation, pancreatitis, severityin pancreatitis and multiple organ failure in animals, preferablyhumans.

[0457] Toxicity

[0458] It is confirmed that the toxicity of the active ingredients andnon-toxic salts thereof and non-toxic acid addition salts thereof in thepresent invention is very weak. For example, LD₅₀ of Compound 1 was117mg/kg when administered intravenously to male mice. Accordingly, theactive substances in the present invention may be considered to besufficiently safe and suitable for pharmaceutical use.

[0459] For the purpose hereinbefore described, the active ingredient inthe present invention and non-toxic salts thereof and non-toxic acidaddition salts thereof may be normally administered systemically orpartially, usually by oral or parenteral administration.

[0460] The doses to be administered are determined depending upon age,weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment, etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, or between 100μg and 100 mg, by parenteral administration (preferably, intravenously)up to several times per day. As mentioned above, the doses to be useddepend upon various conditions. Therefore, there are cases in whichdoses lower than or greater than the ranges specified above may be used.

[0461] Compounds of the present invention are administered in the formof solid compositions, liquid compositions or other compositions fororal administration, and as injections, liniments or suppositories,etc., for parenteral administration.

[0462] Solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders, and granules.

[0463] In such compositions, at least one of the active compounds isadmixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.).

[0464] These compositions may also comprise, as in normal practice,additional substances other than inert diluents: e.g., lubricatingagents (such as magnesium stearate, etc.), disintegrating agents (suchas cellulose calcium glycolate, etc.), assisting agents for dissolving(such as arginine, glutamic acid, asparaginic acid, etc.) andstabilizers (human serum albumin, lactose, etc.).

[0465] The tablets or pills may, if desired, be coated with a film ofgastric or enteric material (such as sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethyl cellulose phthalate, etc.).

[0466] Capsules include hard capsules and soft capsules.

[0467] Liquid compositions for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

[0468] These liquid compositions may comprise inert diluents commonlyused in the art (purified water, ethanol, etc.).

[0469] Besides inert diluents, such compositions may also compriseadjuvants (such as wetting agents, suspending agents, etc.), sweeteningagents, flavoring agents and preserving agents.

[0470] Other compositions for oral administration include spraycompositions, which may be prepared by known methods and which compriseone or more of the active compound(s). Spray compositions may compriseadditional substances other than inert diluents: e.g. stabilizing agents(sodium sulfate, etc.), isotonic stabilizing agents (sodium chloride,sodium citrate, citric acid, etc.). For preparation of such spraycompositions, for example, the method described in the U.S. Pat. No.2,868,691 or No. 3,095,355 may be used.

[0471] Injections for parenteral administration include sterile aqueousor non-aqueous solutions, suspensions and emulsions.

[0472] In such compositions, one or more of active compound(s) is or areadmixed with at least one of inert aqueous diluent(s) (distilled waterfor injection, physiological salt solution, etc.) or inert non-aqueousdiluent(s) (propylene glycol, polyethylene glycol, olive oil, ethanol,POLYSORBATE80 (registered trademark) etc.).

[0473] Injections may comprise furthermore assisting agents such aspreserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agents (such as human serum albumine, lactose, etc.)and assisting agents for dissolving (arginine, glutamic acid,asparaginic acid, polyvinylpyrrolidone, etc.).

[0474] Usually, they may be sterilized by filtration (abacteria-retaining filter etc), by incorporation of sterilizing agentsin the compositions or by irradiation, or after treated, they may alsomanufactured in the form of sterile solid compositions, for example, byfreeze-drying, which may be dissolved in sterile water or some othersterile diluent(s) for injection immediately before used, and which maybe used.

Example

[0475] The following Reference Examples and Examples illustrarte thepresent invention.

[0476] The solvents in parentheses show the developing or elutingsolvents used in chromatographic separations and the solvent ratios usedare by volume.

Example 1 (A)

[0477] Binding Inhibition Against ³H-LTB₄ on the Human PolymorphonuclearLeukocyte (PMN)

[0478] 0.049 ml Hanks balanced salt solution (HBSS), 0.001 ml testcompound and 0.05 ml ³H-LTB₄ (4nM) were added to polypropylene tubes andmixed. The reaction was started by addition of a thoroughly mixed PMNcell suspension (1.6×10⁶ cells), followed by incubation at 0° C. for 20min. The reaction was terminated by the addition of ice-cold HBSS (2.5ml). PMNs were harvested by vacuum filtration through Whatman GF/C glassfiber filters on a Brandel cell harvester (BRANDEL, M-24R). The filterswere then washed 2 times to remove free ³H-LTB₄ with 2.5 ml of theice-cold PBS (−) solution. The filters were transferred to each vial,and equilibrated after adding 8 ml ACS II cocktail (Amersham). Theradioactivity was measured by liquid scintillation counter (Aloka,LSC-5100).

[0479] Specific binding of ³H-LTB₄ to the LTB₄ receptor was defined astotal binding minus nonspecific binding. Nonspecific binding was theamount of ³H-LTB₄ binding in the presence of 1.5 μM LTB₄ instead of thetest compound. The inhibitory effect of test compound was calculatedfrom the following equation.

The percentage of inhibition (%)=100−(B ₁ /B ₀×100)

[0480] B₁: Specific ³H-LTB₄ binding in presence of test compound

[0481] B₀: Specific ³H-LTB₄ binding in absence of test compound

[0482] Results

[0483] The results are shown in the following Table 17. TABLE 17European Patent Publication No. 588655 binding activity Compound No.Compound (Example No.) (%) 1 1 (i) 91.5 2 1 (m) 76.6 3 1 (p) 75.0 4 1(aa) 63.7 5 1 (ii) 94.3 6 1 (pp) 71.6 7 1 (qq) 78.0 8 1 (hhh) 82.7 9 1(lll) 91.6 10 1 (mmm) 86.5 11 2 (g) 76.8 12 2 (p) 95.2 13 2 (u) 100.2 142 (w) 96.5 15 2 (cc) 89.1 16 2 (gg) 83.6 17 2 (kk) 93.9 18 3 (f) 87.0 194 74.0 20 4 (a) 83.5 21 5 (r) 90.8 22 5 (w) 89.7 23 5 (ff) 78.0 24European Patent Publication 61.2 No. 656349 Example 1 (b)

[0484] The structure of compounds used in the present invention areshown below. Compound No. 1

Example 1 (B)

[0485] The compounds of the formula (IB), of the present invention havean antagonistic activity on LTB₄ The results which are measured bymethod as hereinbefore described in Example 1 (A), are shown thefollowing Table 18. TABLE 18 binding activity Compound (Example No.) (%)2 79.7 2 (a) 92.0 2 (b) 97.9 2 (c) 103.2 2 (d) 99.3 2 (e) 94.5 2 (f)91.8 2 (g) 89.6 2 (h) 85.4 2 (i) 69.6 2 (j) 55.4 2 (k) 97.7 2 (l) 81.0 2(m) 89.2 2 (n) 82.8 2 (o) 85.8 2 (p) 95.2 2 (q) 98.0 2 (r) 80.1 2 (s)83.0 2 (t) 51.5 2 (u) 67.6 2 (v) 92.0 2 (w) 76.7 2 (x) 94.1 2 (y) 85.5 2(z) 92.8 2 (aa) 94.4 2 (bb) 87.3 2 (cc) 76.7 2 (dd) 50.8 2 (ee) 65.3 2(ff) 82.4 3 96.8 4 73.1 4 (a) 52.0 5 89.7 5 (a) 62.5 5 (b) 90.2 6 67.8

Example 1 (C)

[0486] Inhibitory Activity on Phospholipase A₂ and on Trypsin

[0487] It has been confirmed that compounds of formula (IB) of thepresent invention have inhibitory activities on phospholipaseA₂ (PLA₂)and on trypsin.

[0488] For example, in laboratory tests the following results wereobtained.

[0489] Method

[0490] (1) Inhibitory Activity on PLA₂

[0491] A reaction solution including 50 mM tris-HCl buffer (pH7.5, 874μl; containing 100 mM sodium chloride, 1 mM EDTA), 1M calciumchloride (6μl), 1% bovine serum albumin (10 μl) and 2.5 mM 10PY-PC (10 μl), wasprepared. To the solution were added a test compound in variousconcentration or water (50 μl), and a solution of 10 mU/ml PLA₂ (derivedfrom hog pancreas) (501 μl). The appearance of fluorescence was measured(Ex=345 nm, Em=396 nm). Percentage (%) of the strength of fluorescencein the presence of a test compound was calculated when the strength ofthat in the absence thereof was regarded as 100%, and therefrom IC₅₀value was calculated. The results are shown in the following Table19.

[0492] (2) Inhibitory Activity on Trypsin

[0493] To a mixture of a 0.2 M HEPES•sodium hydroxide buffer solution(pH 8.0, 100 μl) and distilled water (640 μl), were added a testcompound in various concentration or water (10 μl), and a solution of 80mU/ml trypsin (derived from bovine pancreas) (50 μl) and then themixture was preincubated for one minute at 30° C. To the solution thusobtained was added 2.5 mM BAPNA (200 μl) and the mixture was incubatedat 30° C. The absorbance at 405 nm was measured. Percentage (%) of theabsorbance in the presence of a test compound was calculated when theabsorbance in the absence thereof was regarded as 100%, and therefromIC₅₀ value was calculated. The results are shown in the following Table19. TABLE 19 inhibitory activity inhibitory activity Compound on PLA₂ ontrypsin (Example No.) IC₅₀ (μM) IC₅₀ (μM) 2 — 0.19 2(a) 2.6 0.4 2(b) 3.80.56 2(c) 8.1 0.26 2(d) 8.7 0.14 2(e) 8.5 0.34 2(f) 70 0.10 2(g) 53 0.162(h) 11 0.15 2(i) 59 0.14 2(j) — 0.12 2(k) 20 0.10 2(l) 94 0.12 2(m) 180.17 2(n) 10 0.16 2(o) 12 0.14 2(p) 29 0.13 2(q) 34 0.16 2(r) 46 0.162(s) 44 0.16 3 4.7 0.12 4 41 0.16 4(a) — 0.14 5 — 0.13 5(a) — 0.15 6 4.50.17

[0494] In the methods hereinbefore described,

[0495] 10PY-PC represents3′-palmitoyl-2-(1-pyrenedecanoyl)-L-α-phosphatidylcholine,

[0496] HEPES represents 4-2-hydroxyethyl)-1-piperazineethanesulfonicacid, and BAPNA represents α-N-benzoyl-DL-arginine-p-nitroanilidehydrochloride.

What we claim is:
 1. A new amidinophenol derivative of formula (IB):

is a group of the formula

wherein R⁰ is hydrogen, or C1-4 alkyl, or C1-4 alkoxy, and R¹⁰⁰ and R²⁰⁰each independently is hydrogen or C1-4 alkyl; T is NH or oxygen; E is asingle bond or a group of the formula:

wherein R³⁰⁰ and R⁴⁰⁰ each independently, is hydrogen or C1-4 alkyl A₀is a single bond, C1-4 alkylene, -oxy-(C1-4)alkylene-,-thio-(C1-4)alkylene-, C2-8 alkenylene, or C2-8 alkenylene substitutedby carboxy or by C1-4 alkoxycarbonyl; R is a group of the formula:

is a 4-10 membered hetero ring containing one or two nitrogen atoms,R⁵⁰, R⁶⁰ and R⁷⁰ each independently, is, (i) hydrogen, (ii) C1-8 alkyl,(iii) C2-8 alkenyl (iv) —COOR¹¹⁰ (in which R¹¹⁰ is hydrogen or C1-4alkyl optionally substituted by phenyl), (v) —(C1-8 alkylene)-COOR¹¹⁰(in which R¹¹⁰ has the same meaning as heinbefore defined), (vi) —(C2-8alkenylene)-COOR¹¹⁰ (in which R¹¹⁰ is the same meaning as hereinbeforedefined), (vii) C4-7 cycloalkyl, (viii) —(C1-4 alkylene)-(4-7 memberedhetero ring containing one oxygen), (ix) —(C1-4 alkylene)-(4-7 memberedhetero ring containing one nitrogen), (x) phenyl, (xi) C1-8 alkylsubstituted by one or two phenyl, (xii) —(C1-4 alkylene)-O-benzoyl,(xiii) —(C1-4 alkylene)-CONH-(C1-4 alkylene)-NR¹²⁰R¹³⁰, (xiv) —(C1-4alkylene)-COO—(C1-4 alkylene)-NR¹²⁰R¹³⁰, (xv) —(C1-4alkylene)-COO-amidinophenyl, (xvi) —(C1-4 alkylene)-CONH—(C1-4 alkylsubstituted by one or two COOR¹¹⁰) (in which R¹¹⁰ has the same meaningas hereinbefore defined), (xvii) —(C1-4 alkylene)-CONR¹²⁰R¹³⁰, or(xviii) (C1-4) alkoxy (C1-4) alkyl, R⁸⁰ and R⁹⁰ each independently, isC1-4 alkyl or —(C1-4 alkylene)-phenyl, R¹²⁰ and R¹³⁰ each independently,is hydrogen, C1-4 alkyl, or C2-8 alkenyl, with the provisos that: (1)R⁵⁰ and R⁶⁰ in the formulae (i) and (iii), and R⁵⁰, R⁶⁰ and R⁷⁰ in theformulae (ii) and (iv), are not hydrogen at the same time, (2) when atleast one substituent in R⁵⁰, R⁶⁰, R⁷⁰ and A₀ is a substituentcontaining —COO-t-Bu, the other groups are not groups containingcarboxy, (3) R¹²⁰ and R¹³⁰ are not hydrogen at the same time, (4) when Tis oxygen, the group

E is a single bond, A₀ is a single bond, C1-4 alkylene or vinyleneoptionally substituted by one or two C1-4 alkyl, and R is

 then at least one group in R⁵⁰, R⁶⁰ and R⁷⁰ is (viii) —(C1-4alkylene)-(4-7 membered hetero ring containing one oxygen), (ix) —(C1-4alkylene)-(4-7 membered hetero ring containing one nitrogen), (x)phenyl, (xi) C1-8 alkyl substituted by one or two phenyl, (xii) —(C1-4alkylene)-O-benzoyl, (xiii) —(C1-4 alkylene)-CONH—(C1-4alkylene)-NR¹²⁰R¹³⁰, (xiv) —(C1-4 alkylene)-COO-(C 1-4alkylene)-NR¹²⁰R¹³⁰, (xv) —(C1-4 alkylene)-COO-amidinophenyl, (xvi)—(C1-4 alkylene)-CONH—(C1-4 alkyl substituted by one or two —COOR¹¹⁰)(in which R¹¹⁰ has the same meaning as hereinbefore defined), (xvii)—(C1-4 alkylene)-CONR¹²⁰R¹³⁰, or (xviii) (C1-4) alkoxy (C1-4)alkyl; (5)when T is oxygen, the formula:

E is bond, A₀ is bond, C1-4 alkylene or vinylene optionally substitutedby one or two C1-4 alkyl, and R is

then R⁵⁰, R⁶⁰ and R⁷⁰ are not hydrogen; or a non-toxic salt thereof or anon-toxic acid addition salt thereof.
 2. A compound according to claim1, wherein R is

in which the various symbols are as defined in claim
 1. 3. A compoundaccording to claim 1, wherein R is

in which the various symbols are as defined in claim
 1. 4. A compoundaccording to claim 1, wherein R is

in which the various symbols are as defined in claim
 1. 5. A compoundaccording to claim 1, wherein R is

in which the various symbols are as defined in claim
 1. 6. A compoundaccording to claim 1, wherein

is a 4-10 membered hetero ring containing one nitrogen.
 7. A compoundaccording to claim 1, wherein

is a 4-10 membered hetero ring containing two nitrogens.
 8. A compoundaccording to claim 1, wherein R⁵⁰, R⁶⁰ and R⁷⁰ each independently, is(i) hydrogen, (ii) C1-8 alkyl, (iii) C2-8 alkenyl (iv)-COOR¹¹⁰, (v)—(C1-8 alkylene)-COOR¹¹⁰, (vi) —(C2-8 alkenylene)-COOR¹¹⁰, (vii) C4-7cycloalkyl, (x) phenyl, (xi) C1-8 alkyl substituted by one or twophenyl, (xii) —(C1-4 alkylene)-O-benzoyl, (xiii) —(C1-4alkylene)-CONH—(C1-4 alkylene)-NR¹²⁰R¹³⁰, (xiv) —(C1-4alkylene)-COO—(C1-4 alkylene)-NR¹²⁰R¹³⁰, (xv) —(C1-4alkylene)-OCO-amidinophenyl, (xvi) —(C1-4 alkylene)-CONH—(C1-4 alkylsubstituted by one or two COOR¹¹⁰), (xvii) —(C1-4 alkylene)-CONR¹²⁰R¹³⁰,or (xviii) (C1-4) alkoxy (C1-4) alkyl in which the various symbols aredefined in claim
 1. 9. A compound according to claim 1, wherein R⁵⁰, R⁶⁰and R⁷⁰ each independently, is (viii) —(C1-4 alkylene)-(4-7 memberedhetero ring containing one oxygen).
 10. A compound according to claim 1,wherein R⁵⁰, R⁶⁰ and R⁷⁰ each independently, is (ix) —(C1-4alkylene)-(4-7 membered hetero ring containing one nitrogen).
 11. Acompound according to claim 1, which is4-(4-amidinophenoxycarbonyl)phenoxyacetic acidN-2-propenyl-N-ethoxycarbonylmethylamide,4-(6-amidino-7,8-dihydro-2-naphthyloxycarbonyl)benzoic acidN-phenyl-N-phenylmethylamide,4-(6-amidino-7,8-dihydro-2-naphthyloxycarbonyl)benzoic acidN-phenyl-N-benzyloxycarbonylmethylamide,4-(6-amidino-7,8-dihydro-2-naphthyloxycarbonyl)benzoic acidN-phenyl-N-ethoxycarbonylmethylamide,4-[4-(2-amidinoethenyl)phenoxycarbonyl]benzoic acidN-phenyl-N-ethoxycarbonylmethylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-(1-(S)-ethoxycarbonyl-2-benzoyloxyethylamide,4-[2-(4-amidinophenoxycarbonyl)ethenyl]benzoic acid N-1-(S),3-bis(ethoxycarbonyl)propylamide,4-[2-(4-amidinophenoxycarbonyl)-1-propenyl]benzoic acid N-1-(S),3-bis(ethoxycarbonyl)propylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-[1,1,4-tris(ethoxycarbonyl)-3-butenyl]amide,4-[4-(2-amidinoethenyl)phenoxycarbonyl]benzoic acidN-ethoxycarbonylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)phenoxyacetic acid N-1-(S),3-bis(ethoxycarbonyl)propylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-1,1,2-tris(ethoxycarbonyl)ethylamide,4-[2-(4-amidinophenoxycarbonyl)-1-propenyl]benzoic acidN-ethoxycarbonylmethyl-N-allylamide,5-[4-(4-amidinophenoxycarbonyl)phenyl]-2,4-pentadienoic acid N-1-(S),3-bis(ethoxycarbonyl)propylamide,5-[4-(4-amidinophenoxycarbonyl)phenyl]-2,4-pentadienoic acidN-ethoxycarbonylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-[1,1-bis(ethoxycarbonyl)-3-butenyl]amide,4-[2-(4-amidinophenoxycarbonyl)-1-methylethenyl]benzoic acid N-1-(S),3-bis(ethoxycarbonyl)propylamide,4-[2-(4-amidinophenoxycarbonyl)-1-methylethenyl]benzoic acidN-ethoxycarbonylmethyl-N-allylamide,3-[4-(4-amidinophenoxycarbonyl)phenyl]-2-ethoxycarbonyl-2-propenoic acidN-1-(S), 3-bis(ethoxycarbonyl)propylamide,3-[4-(4-amidinophenoxycarbonyl)phenyl]-2-ethoxycarbonyl-2-propenoic acidN-ethoxycarbonylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-2-dimethylaminoethylcarbamoylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-2-dimethylaminoethoxycarbonylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-4-amidinophenoxycarbonylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-1,1-bis(ethoxycarbonyl)methylcarbamoylmethyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-(diallylcarbamoyl)methyl-N-allylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-(i-(S)-ethoxycarbonyl-3-methylbutyl)-N-ethoxycarbonylmethylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-3-methylbutyl-N-2-(ethoxycarbonyl)ethylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-cyclohexyl-N-2-carboxyethylamide,4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-2-methoxyethyl-N-ethoxycarbonylmethylamide,4-(4-amidinophenylcarbamoyl)-α-methylcinnamic acidN-allyl-N-carboxymethylamide, or4-(4-amidino-1-methoxyphenoxycarbonyl)benzoic acidN-1,1-bis(phenylmethyl)methyl-N-3-phenylpropylamide.
 12. A compoundaccording to claim 1, which is2-[4-(4-amidinophenoxycarbonyl)phenylmethylimino]-2-(N-benzyl-N-methylamino)aceticacid ethylester, or2-{N-[4-(4-amidinophenoxycarbonyl)phenyl]methyl-N-benzylamino}aceticacid ethyl ester.
 13. A compound according to claim 1, which is ethyl1-[4-(4-amidinophenoxycarbonyl)phenylmethyl]-1-(3-phenylpropyl)phosphinate,or diethyl 2-[4-(4-amidinophonoxycarbonyl)phenyl]ethenylphosphonate. 14.A compound according to claim 1, which is4-(4-amidionophenoxycarbonyl)-α-methylcinnamic acidN-(2,3,4,5-tetrahydro-fran-2-yl)methyl-N-carboxymethylamide.
 15. Acompound according to claim 1, which is4-(4-amidinophenoxycarbonyl)-α-methylcinnamic acidN-(4-piperidinylmethyl)-N-carboxymethylamide.
 16. A compound accordingto claim 1, which is 4-(4-phenylpiperidinylmethyl)benzoic acid4-amidinophenyl ester, or 4-(2-ethoxycarbonylindolylmethyl)benzoic acid4-amidinophenyl ester.
 17. A compound according to claim 1, which is4-(2-phenylimidazolylmethyl)benzoic acid 4-amidinophenyl ester.
 18. Acompound according to calim 1 wherein a compound of the formula (IB) isin the form of a non-toxic acid addition salt.
 19. A process for thepreparation of a compound of formula (IB):

which comprises forming an ester or amide bond between a compound of theformula:

(wherein the various symbols are as defined in claim 1) and a compoundof the formula:

(wherein the various symbols are as defined in claim 1); and optionallyconverting the amidinophenol derivative thus obtained into a salt oracid addition salt thereof.
 20. A method for the prevention and/ortreatment of diseases induced by leukotriene B₄, phospholipaseA₂, ortrypsin, which comprises administering to a patient an effective amountof a compound of the formula (IB) depicted in claim 1 a non-toxic saltthereof, or a non-toxic acid addition salt thereof.
 21. A method for theprevention and/or treatment of diseases induced by leukotriene B₄, whichcomprises administering to a patient an effective amount of a compoundof the formula (IB) depicted in claim 1, a non-toxic salt thereof, or anon-toxic acid addition salt thereof.
 22. A method for the preventionand/or treatment of diseases induced by phospholipaseA₂ or trypsin,which comprises administering to a patient an effective amount of acompound of the formula (IB) depicted in claim 1, a non-toxic saltthereof, or a non-toxic acid addition salt thereof.
 23. A method for theprevention and/or treatment of diseases of inflammation or allergyinduced by leukotriene B₄, which comprises administering to a patient aneffective amount of a compound of the formula (IB) depicted in claim 1,a non-toxic salt thereof, or a non-toxic acid addition salt thereof. 24.A method for the prevention and/or treatment of diseases induced byleukotriene B₄, which comprises the administration to a patient of aneffective amount of a compound of formula (IA):

wherein R¹ and R² each independently, is: (i) hydrogen or (ii) —COOR⁴(in which R⁴ is C1-3 alkyl); A is (i) a single bond, (ii) C1-4 alkylene,or (iii) —C(R⁵)═C(R⁶)— (in which R⁵ and R⁶ each independently, ishydrogen or C1-4 alkyl); R³ is (i) —CON(R⁷)R⁸, (ii) —CONR⁹—CH(R⁷)R⁸, or(iii)

wherein R⁷ and R⁸ each independently, is (1) hydrogen, (2) phenyl, (3)—(C1-4 alkylene)-phenyl, (4) —(C1-4 alkylene)-phenyl which issubstituted by one or two —R⁰-COOR¹² (in which R¹¹ is a single bond orC1-8 alkylene, and R¹² is hydrogen or C1-4 alkyl), (5) C1-5 alkyl, (6)C2-10 alkenyl containing one to three double bonds, (7) —R^(11a)—COOR¹²(in which R^(11a) is (a) a single bond, (b) C1-8 alkylene, (c) C2-8alkenylene, or (d) C4-8 alkenylene in which one or two carbon atoms inthe main chain are replaced by sulfur, and R¹² is hydrogen or C1-4alkyl), or (8) C3-7 cycloalkyl; R⁹ is (1) hydrogen, (2) —R¹¹-COOR¹² (inwhich R¹¹ is a single bond or C1-8 alkylene, and R¹² is hydrogen or C1-4alkyl), or (3) C2-6 alkoxyalkyl; the grouping:

is a 4-7 membered mono hetero ring containing one or two nitrogen; R¹⁰is (1) hydrogen or (2)-(C1-4 alkylene)-phenyl, with the proviso that:(1) both R⁷ and R⁸ are not hydrogen at the same time, (2) when at leastone of R⁷, R⁸ or R⁹ is a group containing —COO-t-Bu, the other groups donot contain carboxy; or a non-toxic salt thereof, or a non-toxic acidaddition salt thereof.
 25. A method for the prevention and/or treatmentof diseases of inflammation or allergy induced by leukotriene B₄, whichcomprises administering to a patient an effective amount of a compoundof the formula (IA) depicted in claim 24, a non-toxic salt thereof, or anon-toxic acid addition salt thereof.
 26. A pharmaceutical compositionwhich comprises, as active ingredient, an effective amount of a compoundof the formula (IB) depicted in claim 1, a non-toxic salt thereof, or anon-toxic acid addition salt thereof, with a carrier or coating.